Novel indazole derivatives

ABSTRACT

An object of the present invention is to create a novel indazole derivative useful as a drug and to find a novel pharmacological action of the derivative. The compound of the present invention is represented by the formula [I] and has an excellent Rho kinase inhibiting action. In the formula, a ring X is a benzene ring or a pyridine ring; R 1  and R 2  are H or alkyl; R 3  and R 4  are halogen, H, OH, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, aryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, carboxy, hydrocarbonyl, alkylcarbonyl, etc.; and R 5  is halogen atom, H, OH, alkoxy, aryloxy, alkyl or aryl. Each group can be substituted.

TECHNICAL FIELD

The present invention relates to a novel indazole derivative or a saltthereof useful as a pharmaceutical. The indazole derivative according tothe present invention has a Rho kinase inhibiting action and is usefulas a treating agent for diseases in which Rho kinase is involved such aseye diseases including glaucoma.

BACKGROUND ART

Rho, a low-molecule GTP-binding protein, is activated by signals fromvarious cell membrane receptors. The activated Rho functions, via Rhokinase signal transduction and actomyosin signal transduction, as amolecular switch for various cellular phenomena such as contraction ofsmooth muscles, morphological changes in cells, cell movement, celldivision, intercellular adhesion, platelet aggregation, leukocyteaggregation, infiltration and increase of cancer cells.

It has been also known that such cellular phenomena deeply participatein diseases such as hypertension, angina pectoris, asthma, peripheralcircular disorder, premature delivery, arteriosclerosis, cancer,inflammatory diseases, autoimmune diseases, AIDS, fertilization andimplantation of a fertilized egg, osteoporosis, cerebral functiondisturbance, gastrointestinal dyfunction by bacteria, glaucoma andretinopathy.

Accordingly, it is believed that, when Rho is inhibited, preventionand/or treatment of the aforementioned diseases in which Rho isparticipated are/is possible.

On the other hand, it has been also known that, when Rho kinase, whichexists in the downstream of signal transduction mediated by Rho, isinhibited, various cellular phenomena caused by Rho are able to besuppressed.

Thus, compounds which inhibit the Rho kinase are believed to beeffective preventive and/or treating agents for the aforementioneddiseases in which Rho is participated such as hypertension, anginapectoris, asthma, peripheral circular disorder, premature delivery,arteriosclerosis, cancer, inflammatory diseases, autoimmune diseases,AIDS, fertilization and implantation of fertilized egg, osteoporosis,cerebral function disturbance, gastrointestinal dyfunction by bacteria,glaucoma and retinopathy (WO 98/06433).

A Rho kinase inhibitor is usually defined as an inhibitor forserine/threonine kinase activated as a result of activation of Rho. TheRho kinase inhibitor, includes compounds which inhibit protein havingserine/threonine kinase activity such as ROKα (ROCK-II), ROKβ (ROCK-I,p160ROCK) and others.

Examples of the known Rho kinase inhibitor are amide derivativesdisclosed in WO 98/06433; isoquinoline sulfonyl derivatives disclosed inWO 97/23222, Nature 389, 990-994 (1997) and WO 99/64011; heterocyclicamino derivatives disclosed in WO 01/56988; indazole derivativesdisclosed in WO 02/100833; and quinazoline derivatives disclosed in WO02/076976 and WO 02/076977.

It has been also disclosed in WO 00/09162 and WO 00/57914 that a Rhokinase inhibitor is useful as a treating agent for glaucoma.

However, in any of the aforementioned documents, there is no specificdisclosure for the indazole derivative according to the presentinvention.

DISCLOSURE OF THE INVENTION

It is a very interesting matter to create novel indazole derivativeswhich are useful as pharmaceuticals and to find new pharmacologicalactions of such derivatives.

In order to solve the above matter, the present inventors have madesynthetic studies for novel indazole derivatives and have succeeded increating many novel compounds.

Further, when usefulness of the indazole derivatives of the presentinvention as pharmaceuticals has been variously investigated, it hasbeen found that-the present indazole derivatives have a Rho kinaseinhibiting action and are useful as treating agents for diseases inwhich Rho kinase is involved.

Further, in order to check the application of the present indazolederivatives to specific diseases in which Rho is involved, anintraocular pressure-reducing action of the present indazole derivativeswas also studied. As a result, it was found that the present indazolederivatives exhibited an excellent intraocular pressure-reducing actionand are useful as treating agents for eye diseases such as glaucoma, andwhereupon the present invention has been achieved.

Thus, the present invention relates to a compound represented by thefollowing formula [I] or a salt thereof (hereinafter, that will bereferred to as “the present invention compound” unless otherwise stated)and also to a pharmaceutical composition containing the presentinvention compound. In particular, the present invention relates to aRho kinase inhibitor comprising the present invention compound as anactive ingredient and further to a treating agent for eye diseases suchas glaucoma.

The present invention compound has the chemical structuralcharacteristics as shown in the following 1) to 4).

1) An indazole ring is a main skeleton.

2) A ring X is directly bonded to an indazole ring.

3) A ring X has an amino-substituted alkyl group or cycloalkyl group.

4) In the above 3), the amino group is located at 1-position of thealkyl group or the cycloalkyl group.

Each of the chemical structural characteristics of 1) to 4) as suchand/or a combination thereof are/is important in achievement of the Rhokinase inhibiting action of the present invention compound.

Further, in addition to the aforementioned 1) to 4), the presentinvention compound where

5) the carbon atom in which the amino group of the above 3) isintroduced is not an asymmetric carbon atom

exhibits a particularly good Rho kinase inhibiting action.

[In the formula, a ring X is a benzene ring or a pyridine ring;

R¹ and R² are, the same or different, hydrogen atom or a substituted orunsubstituted alkyl group;

R¹ and R² can be bonded to form a substituted or unsubstitutedcycloalkane ring;

R³ and R⁴ are, the same or different, one or more group(s) selected fromthe group consisting of halogen atom, hydrogen atom, hydroxyl group, asubstituted or unsubstituted alkoxy group, a substituted orunsubstituted alkenyloxy group, a substituted or unsubstitutedalkynyloxy group, a substituted or unsubstituted cycloalkyloxy group, asubstituted or unsubstituted cycloalkenyloxy group, a substituted orunsubstituted aryloxy group, a substituted or unsubstituted alkyl group,a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group, a substituted or unsubstituted cycloalkylgroup, a substituted or unsubstituted cycloalkenyl group, a substitutedor unsubstituted aryl group, carboxyl group or an ester or an amidethereof, hydrocarbonyl group, a substituted or unsubstitutedalkylcarbonyl group, a substituted or unsubstituted arylcarbonyl group,amino group, a substituted or unsubstituted alkylamino group, asubstituted or unsubstituted arylamino group, mercapto group, asubstituted or unsubstituted alkylthio group, a substituted orunsubstituted arylthio group, sulfinic acid group or an ester or anamide thereof, hydrosulfinyl group, a substituted or unsubstitutedalkylsulfinyl group, a substituted or unsubstituted arylsulfinyl group,sulfonic acid group or an ester or an amide thereof, hydrosulfonylgroup, a substituted or unsubstituted alkylsulfonyl group, a substitutedor unsubstituted arylsulfonyl group, nitro group, cyano group and asubstituted or unsubstituted monocyclic heterocylic group;

R⁵ is one or more group(s) selected from the group consisting of halogenatom, hydrogen atom, hydroxyl group, a substituted or unsubstitutedalkoxy group, a substituted or unsubstituted aryloxy group, asubstituted or unsubstituted alkyl group and a substituted orunsubstituted aryl group;

and, hereinafter, they have the same meanings.]

The present invention provides a novel indazole derivative or a saltthereof which is useful as a pharmaceutical. In particular, the presentinvention compound exhibits an excellent Rho kinase inhibiting actionand is useful as a treating agent for diseases in which Rho kinase isinvolved such as eye diseases including glaucoma.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph which shows the changes in intraocular pressure ineach administration group with lapse of time. The intraocular pressureis shown by the pressure change from the initial intraocular pressure. □shows the group to which the test compound 1 was administered and oshows a control group.

FIG. 2 is a graph which shows the changes in intraocular pressure ineach administration group with lapse of time. The intraocular pressureis shown by the pressure change from the initial intraocular pressure. □shows the group to which the test compound 2 was administered and oshows a control group.

FIG. 3 is a graph which shows the changes in intraocular pressure ineach administration group with lapse of time. The intraocular pressureis shown by the pressure change from the initial intraocular pressure. □shows the group to which the test compound 3 was administered and oshows a control group.

FIG. 4 is a graph which shows the changes in intraocular pressure ineach administration group with lapse of time. The intraocular pressureis shown by the pressure change from the initial intraocular pressure. □shows the group to which the test compound 4 was administered and oshows a control group.

BEST MODE FOR CARRYING OUT THE INVENTION

Each of the rings, atoms or groups which are described in the presentspecification will now be illustrated in detail as hereunder.

“A cycloalkane group” is a cycloalkane group having 3 to 8 carbon atoms.Specific examples thereof are cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane and cyclooctane.

“A monocyclic heterocycle” is a saturated or unsaturated monocyclicheterocycle having one or more hetero atom(s) selected from nitrogenatom, oxygen atom and sulfur atom in a ring.

Specific examples of the saturated monocyclic heterocycle are thathaving nitrogen atom in a ring such as pyrrolidine, pyrazolidine,imidazolidine, triazolidine, piperidine, hexahydropyridazine,hexahydropyrimidine, piperazine, homopiperidine and homopiperazine; thathaving oxygen atom in a ring such as tetrahydrofuran andtetrahydropyran; that having sulfur atom in a ring such astetrahydrothiophene and tetrahydrothiopyran; that having nitrogen atomand oxygen atom in a ring such as oxazolidine, isoxazolidine andmorpholine; and that having nitrogen atom and sulfur atom in a ring suchas thiazolidine, isothiazolidine and thiomorpholine.

Specific examples of the unsaturated monocyclic heterocycle are thathaving nitrogen atom in a ring such as dihydropyrrole, pyrrole,dihydropyrazole, pyrazole, dihydroimidazole, imidazole, dihydrotriazole,triazole, tetrahydropyridine, dihydropyridine, pyridine,tetrahydropyridazine, dihydropyridazine, pyridazine,tetrahydropyrimidine, dihydropyrimidine, pyrimidine, tetrahydropyrazine,dihydropyrazine and pyrazine; that having oxygen atom in a ring such asdihydrofuran, furan, dihydropyran and pyran; that having sulfur atom ina ring such as dihydrothiophene, thiophene, dihydrothiopyran andthiopyran; that having nitrogen atom and oxygen atom in a ring such asdihydrooxazole, oxazole, dihydroisoxazole, isoxazole, dihydrooxazine andoxazine; and that having nitrogen atom and sulfur atom in a ring such asdihydrothiazole, thiazole, dihydroisothiazole, isothiazole,dihydrothiazine and thiazine.

“Halogen atom” is fluorine, chlorine, bromine or iodine.

“Alkyl” is a straight or branched alkyl having 1 to 6 carbon atom(s).Specific examples thereof are methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl andisopentyl.

“Alkoxyl” is a straight or branched alkoxyl having 1 to 6 carbonatom(s). Specific examples thereof are methoxy, ethoxy, n-propoxy,n-butoxy, n-pentoxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy,tert-butoxy and isopentoxy.

“Alkenyloxy” is a straight or branched alkenyloxy having 2 to 8 carbonatoms. Specific examples thereof are vinyloxy, allyloxy, 1-propenyloxy,3-butenyloxy, 3-pentenyoxy, 4-hexenyloxy, 5-heptenyloxy, 7-octenyloxyand 1-methylvinyloxy.

“Alkynyloxy” is a straight or branched alkynyloxy having 2 to 8 carbonatoms. Specific examples thereof are ethynyloxy, 2-propynyloxy,2-butynyloxy, 3-pentynyloxy, 4-hexynyloxy, 5-heptynyloxy, 7-octynyloxyand 2-methylbutynyloxy.

“Cycloalkyloxy” is a cycloalkyloxy having 3 to 8 carbon atoms. Specificexamples thereof are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

“Cycloalkenyloxy” is a cycloalkenyloxy having 3 to 8 carbon atoms.Specific examples thereof are cyclopropenyloxy, cyclobutenyloxy,cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy and cyclooctenyloxy.

“Aryloxy” is a monocyclic or a di-cyclic or tri-cyclic fused polycyclicaromatic hydrocarbonoxy having 6 to 14 carbon atoms. Specific examplesthereof are phenoxy, naphthyloxy, anthryloxy and phenanthryloxy.

“Alkenyl” is a straight or branched alkenyl having 2 to 8 carbon atoms.Specific examples thereof are vinyl, allyl, 1-propenyl, 3-butenyl,3-pentenyl, 4-hexenyl, 5-heptenyl, 7-octenyl and 1-methylvinyl.

“Alkynyl” is a straight or branched alkynyl having 2 to 8 carbon atoms.Specific examples thereof are ethynyl, 2-propynyl, 2-butynyl,3-pentynyl, 4-hexynyl, 5-heptynyl, 7-octynyl and 2-methylbutynyl.

“Cycloalkyl” is a cycloalkyl having 3 to 8 carbon atoms. Specificexamples thereof are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

“Cycloalkenyl” is a cycloalkenyl having 3 to 8 carbon atoms. Specificexamples thereof are cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl and cyclooctenyl.

“Aryl” is a monocyclic or di-cyclic or tri-cyclic fused polycyclicaromatic hydrocarbon having 6 to 14 carbon atoms. Specific examplesthereof are phenyl, naphthyl, anthryl and phenanthryl.

“Ester of carboxyl group” is an ester comprising carboxyl group residuewith an alkyl alcohol, aryl alcohol, etc. Specific examples of the alkylalcohol are methanol, ethanol, propanol and butanol and specificexamples of the aryl alcohol are phenol and naphthol.

“Amide of carboxyl group” is an amide comprising carboxyl group residuewith ammonia, primary or secondary amine, etc. The amine can be eitheran alkylamine or an arylamine and specific examples of the alkylamineare methylamine, ethylamine, ethylmethylamine, dimethylamine,diethylamine and dihexylamine while specific examples of the arylamineare aniline, naphthylamine, methylphenylamine, ethylphenylamine anddiphenylamine.

“Alkylcarbonyl” is a straight or branched alkylcarbonyl having 2 to 7carbon atoms. Specific examples thereof are methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl,n-hexylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl,tert-butylcarbonyl and isopentylcarbonyl.

“Arylcarbonyl” is a monocyclic or di-cyclic or tri-cyclic fusedpolycyclic aromatic hydrocarbon carbonyl having 7 to 15 carbon atoms.Specific examples thereof are phenylcarbonyl, naphthylcarbonyl,anthrylcarbonyl and phenanthrylcarbonyl.

“Alkylamino” is a mono- or dialkylamino. Specific examples thereof aremethylamino, ethylamino, ethyl methylamino, dimethylamino, diethylaminoand dihexylamino.

“Arylamino” is a mono- or diarylamino. Specific examples thereof arephenylamino, naphthylamino, methyl phenylamino, ethyl phenylamino anddiphenylamino.

“Alkylthio” is a straight or branched alkylthio having 1 to 6 carbonatom(s). Specific examples thereof are methylthio, ethylthio,n-propylthio, n-butylthio, n-pentylthio, n-hexylthio, isopropylthio,isobutylthio, sec-butylthio, tert-butylthio and isopentylthio.

“Arylthio” is a monocyclic or a di-cyclic or tri-cyclic fused polycyclicaromatic hydrocarbon thio having 6 to 14 carbon atoms. Specific examplesthereof are phenylthio, naphthylthio, anthrylthio and phenanthrylthio.

“Ester of sulfinic acid group” is an ester formed from sulfinic acidgroup and alkyl alcohol, aryl alcohol, etc. Specific examples of thealkyl alcohol are methanol, ethanol, propanol and butanol while specificexamples of the aryl alcohol are phenol and naphthol.

“Amide of sulfinic amide group” is an amide formed from sulfinic acidand ammonia, a primary or second amine, etc. The amine can be eitheralkylamine or arylamine and specific examples of the alkylamine aremethylamine, ethylamine, ethyl methylamine, dimethylamine, diethylamineand dihexylamine while specific examples of the arylamine are aniline,naphthylamine, methyl phenylamine, ethyl phenylamine and diphenylamine.

“Alkylsulfinyl” is a straight or branched alkylsulfinyl having 1 to 6carbon atom(s). Specific examples thereof are methylsulfinyl,ethylsulfinyl, n-propylsulfinyl, n-butylsulfinyl, n-pentylsulfinyl,n-hexylsulfinyl, isopropylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl,tert-butylsulfinyl and isopentylsulfinyl.

“Arylsulfinyl” is a monocyclic or a di-cyclic or tri-cyclic fusedpolycyclic aromatic hydrocarbon sulfinyl having 6 to 14 carbon atoms.Specific examples thereof are phenylsulfinyl, naphthylsulfinyl,anthrylsulfinyl and phenanthrylsulfinyl.

“Ester of sulfonic acid group” is an ester formed from sulfonic acidgroup and alkyl alcohol, aryl alcohol, etc. Specific examples of thealkyl alcohol are methanol, ethanol, propanol and butanol while specificexamples of the aryl alcohol are phenol and naphthol.

“Amide of sulfonic acid group” is an amide formed from sulfonic acidgroup and ammonia, a primary or secondary amine, etc. The amine may beeither alkylamine or arylamine and specific examples of the alkylamineare methylamine, ethylamine, ethyl methylamine, dimethylamine,diethylamine and dihexylamine while specific examples of the arylamineare aniline, naphthylamine, methyl phenylamine, ethyl phenylamine anddiphenylamine.

“Alkylsulfonyl” is a straight or branched alkylsulfonyl having 1 to 6carbon atom(s). Specific examples thereof are methylsulfonyl,ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl, n-pentylsulfonyl,n-hexylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, sec-butylsulfoyl,tert-butylsulfonyl and isopentylsulfonyl.

“Arylsulfonyl” is a monocyclic or a di-cyclic or tri-cyclic fusedpolycyclic aromatic hydrocarbon sulfonyl having 6 to 14 carbon atoms.Specific examples thereof are phenylsulfonyl, naphthylsulfonyl,anthrylsulfonyl and phenanthrylsulfonyl.

“Alkoxyimino” is a straight or branched alkoxyimino having 1 to 6 carbonatom(s). Specific examples thereof are methoxyimino, ethoxyimino,n-propoxyimino, n-butoxyimino, n-pentoxyimino, n-hexyloxyimino,isopropoxyimino, isobutoxyimino, sec-butoxyimino, tert-butoxyimino andisopentoxyimino.

“Aryloxyimino” is a monocyclic or di- or tricyclic fused polycyclicaromatic hydrocarbon oxyimino having 6 to 14 carbon atom(s). Specificexamples thereof are phenoxyimino, naphthyloxyimino, anthryloxyimino andphenanthryloxyimino.

“Substituted cycloalkane ring” is a cycloalkane ring having one or moregroup(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, alkyl group, cycloalkyl group, aryl group, carboxyl groupor ester or amide thereof, amino group, alkylamino group, arylaminogroup, nitro group and cyano group as substituent(s).

“Substituted monocyclic heterocycle” is a monocyclic heterocylic grouphaving one or more group(s) selected from halogen atom, hydroxyl group,alkoxy group, aryloxy group, alkyl group, cycloalkyl group, aryl group,carboxy group or an ester or an amide thereof, amino group, alkylaminogroup, arylamino group, mercapto group, alkylthio group, arylthio group,formyl group, alkylcarbonyl group, arylcarbonyl group, nitro group andcyano group as substituent(s).

“Substituted alkyl group” is an alkyl group having one or more group(s)selected from halogen atom, hydroxyl group, alkoxy group, aryloxy group,cycloalkyl group, aryl group, aryl group substituted with halogen atom,aryl group substituted with alkoxy group, carboxy group or an ester oran amide thereof, amino group, alkylamino group, arylamino group, nitrogroup, cyano group, hydroxyimino group, alkoxyimino group andaryloxyimino group as substituent(s).

“Substituted alkoxy group” is an alkoxy group having one or moregroup(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, cycloalkyl group, aryl group, aryl group substituted withhalogen atom, aryl group substituted with alkoxy group, carboxy group oran ester or an amide thereof, amino group, alkylamino group, arylaminogroup, nitro group, cyano group, hydroxyimino group, alkoxyimino groupand aryloxyimino group as substituent(s).

“Substituted alkenyloxy group” is an alkenyloxy group having one or moregroup(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, cycloalkyl group, aryl group, aryl group substituted withhalogen atom, aryl group substituted with alkoxy group, carboxy group oran ester or an amide thereof, amino group, alkylamino group, arylaminogroup, nitro group and cyano group as substituent(s).

“Substituted alkynyloxy group” is an alkynyloxy group having one or moregroup(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, cycloalkyl group, aryl group, aryl group substituted withhalogen atom, aryl group substituted with alkoxy group, carboxy group oran ester or an amide thereof, amino group, alkylamino group, arylaminogroup, nitro group and cyano group as substituent(s).

“Substituted cycloalkyloxy group” is a cycloalkyloxy group having one ormore group(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, alkyl group, cycloalkyl group, aryl group, carboxy groupor an ester or an amide thereof, amino group, alkylamino group,arylamino group, nitro group and cyano group as substituent(s).

“Substituted cycloalkenyloxy group” is a cycloalkenyloxy group havingone or more group(s) selected from halogen atom, hydroxyl group, alkoxygroup, aryloxy group, alkyl group, cycloalkyl group, aryl group, carboxygroup or an ester or an amide thereof, amino group, alkylamino group,arylamino group, nitro group and cyano group as substituent(s).

“Substituted aryloxy group” is an aryloxy group having one or moregroup(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, alkyl group, cycloalkyl group, aryl group, carboxy groupor an ester or an amide thereof, amino group, alkylamino group,arylamino group, nitro group and cyano group as substituent(s).

“Substituted alkenyl group” is an alkenyl group having one or moregroup(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, cycloalkyl group, aryl group, aryl group substituted withhalogen atom, aryl group substituted with alkoxy group, carboxy group oran ester or an amide thereof, amino group, alkylamino group, arylaminogroup, nitro group, cyano group, hydroxyimino group, alkoxyimino groupand aryloxyimino group as substituent(s).

“Substituted alkynyl group” is an alkynyl group having one or moregroup(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, cycloalkyl group, aryl group, aryl group substituted withhalogen atom, aryl group substituted with alkoxy group, carboxy group oran ester or an amide thereof, amino group, alkylamino group, arylaminogroup, nitro group and cyano group as substituent(s).

“Substituted cycloalkyl group” is a cycloalkyl group having one or moregroup(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, alkyl group, cycloalkyl group, aryl group, carboxy groupor an ester or an amide thereof, amino group, alkylamino group,arylamino group, nitro group and cyano group as substituent(s).

“Substituted cycloalkenyl group” is a cycloalkenyl group having one ormore group(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, alkyl group, cycloalkyl group, aryl group, carboxy groupor an ester or an amide thereof, amino group, alkylamino group,arylamino group, nitro group and cyano group as substituent(s).

“Substituted aryl group” is an aryl group having one or more group(s)selected from halogen atom, hydroxyl group, alkoxy group, aryloxy group,alkyl group, cycloalkyl group, aryl group, carboxy group or an ester oran amide thereof, amino group, alkylamino group, arylamino group, nitrogroup, cyano group, hydroxyimino group, alkoxyimino group andaryloxyimino group as substituent(s).

“Substituted alkylcarbonyl group” is an alkylcarbonyl group having oneor more group(s) selected from halogen atom, hydroxyl group, alkoxygroup, aryloxy group, cycloalkyl group, aryl group, aryl groupsubstituted with halogen atom, aryl group substituted with alkoxy group,carboxy group or an ester or an amide thereof, amino group, alkylaminogroup, arylamino group, nitro group and cyano group as substituent(s).

“Substituted arylcarbonyl group” is an arylcarbonyl group having one ormore group(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, alkyl group, cycloalkyl group, aryl group, carboxy groupor an ester or an amide thereof, amino group, alkylamino group,arylamino group, nitro group and cyano group as substituent(s).

“Substituted alkylamino group” is an alkylamino group in which an alkylmoiety thereof has one or more group(s) selected from halogen atom,hydroxyl group, alkoxy group, aryloxy group, cycloalkyl group, arylgroup, aryl group substituted with halogen atom, aryl group substitutedwith alkoxy group, carboxy group or an ester or an amide thereof, aminogroup, alkylamino group, arylamino group, nitro group and cyano group assubstituent(s).

“Substituted arylamino group” is an arylamino group in which an arylmoiety thereof has one or more group(s) selected from halogen atom,hydroxyl group, alkoxy group, aryloxy group, alkyl group, cycloalkylgroup, aryl group, carboxy group or an ester or an amide thereof, aminogroup, alkylamino group, arylamino group, nitro group and cyano group assubstituent(s).

“Substituted alkylthio group” is an alkylthio group having one or moregroup(s) selected from halogen atom, hydroxyl group, alkoxy group,aryloxy group, cycloalkyl group, aryl group, aryl group substituted withhalogen, aryl group substituted with alkoxy group, carboxy group or anester or an amide thereof, amino group, alkylamino group, arylaminogroup, nitro group and cyano group as substituent(s).

“Substituted arylthio group” is an arylthio group in which an arylmoiety thereof has one or more group(s) selected from halogen atom,hydroxyl group, alkoxy group, aryloxy group, alkyl group, cycloalkylgroup, aryl group, carboxy group or an ester or an amide thereof, aminogroup, alkylamino group, arylamino group, nitro group and cyano group assubstituent(s).

“Substituted alkylsulfinyl group” is an alkylsulfinyl group having oneor more group(s) selected from halogen atom, hydroxyl group, alkoxygroup, aryloxy group, cycloalkyl group, aryl group, aryl groupsubstituted with halogen, aryl group substituted with alkoxy group,carboxy group or an ester or an amide thereof, amino group, alkylaminogroup, arylamino group, nitro group and cyano group as substituent(s).

“Substituted arylsulfinyl group” is an arylsulfinyl group in which anaryl moiety thereof has one or more group(s) selected from halogen atom,hydroxyl group, alkoxy group, aryloxy group, alkyl group, cycloalkylgroup, aryl group, carboxy group or an ester or an amide thereof, aminogroup, alkylamino group, arylamino group, nitro group and cyano group assubstituent(s).

“Substituted alkylsulfonyl group” is an alkylsulfonyl group having oneor more group(s) selected from halogen atom, hydroxyl group, alkoxygroup, aryloxy group, cycloalkyl group, aryl group, aryl groupsubstituted with halogen, aryl group substituted with alkoxy group,carboxy group or an ester or an amide thereof, amino group, alkylaminogroup, arylamino group, nitro group and cyano group as substituent(s).

“Substituted arylsulfonyl group” is an arylsulfonyl group in which anaryl moiety thereof has one or more group(s) selected from halogen atom,hydroxyl group, alkoxy group, aryloxy group, alkyl group, cycloalkylgroup, aryl group, carboxy group or an ester or an amide thereof, aminogroup, alkylamino group, arylamino group, nitro group and cyano group assubstituent(s).

When the present invention compound has free hydroxyl group, aminogroup, alkylamino group or arylamino group as a substituent, such agroup may be protected by a protective group.

Examples of the protective group for a free hydroxyl group are thosewhich have been commonly used as protective groups for free hydroxylgroup including a substituted or unsubstituted alkyl group or anunsubstituted alkenyl group such as methoxymethyl group, benzyl group,trityl group, 4-methoxyphenylmethyl group, benzyloxymethyl group, methylgroup and allyl group; a substituted or unsubstituted heterocyclic groupsuch as 3-bromotetrahydropyranyl group, tetrahydropyranyl group andtetrahydrofuranyl group; a substituted or unsubstituted alkylcarbonylgroup or a substituted or unsubstituted arylcarbonyl group such astrifluoroacetyl group, acetyl group, 4-chlorobenzoyl group and benzoylgroup; a substituted or unsubstituted alkyloxycarbonyl group, anunsubstituted alkenyloxycarbonyl group or a substituted or unsubstitutedaryloxycarbonyl group such as benzyloxycarbonyl group,4-methoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group,methoxycarbonyl group, ethoxycarbonyl group, isobutoxycarbonyl group,tert-butoxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonylgroup, 4-nitrophenyloxycarbonyl group and phenyloxycarbonyl group; and asubstituted silyl group such as trimethylsilyl group, triethylsilylgroup, triisopropylsilyl group, tert-butyldimethylsilyl group andtert-butyldiphenylsilyl group.

Examples of the protective group for free amino group, alkylamino groupor arylamino group are those which have been commonly used as protectivegroups for free amino group, alkylamino group or arylamino groupincluding a substituted alkyl group or an unsubstituted alkenyl groupsuch as benzyl group, trityl group, diphenylmethyl group,(4-methoxyphenyl)diphenylmethyl group and allyl group; hydrocarbonylgroup is formyl group; a substituted or unsubstituted alkylcarbonylgroup, a substituted or unsubstituted arylcarbonyl group or anunsubstituted heterocyclic carbonyl group such as trichloroacetyl group,trifluoroacetyl group, acetyl group, 4-chlorobenzoyl group, benzoylgroup and picolinoyl group; a substituted or unsubstitutedalkyloxycarbonyl group or a substituted or unsubstituted aryloxycarbonylgroup such as 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonylgroup, diphenylmethoxycarbonyl group, methoxycarbonyl group,isobutoxycarbonyl group, tert-butoxycarbonyl group,3-nitrophenoxycarbonyl group and phenoxycarbonyl group; and asubstituted or unsubstituted alkylsulfonyl group or a substituted orunsubstituted arylsulfonyl group such as benzylsulfonyl group,tolylsulfonyl group, methylsulfonyl group, 4-chlorophenylsulfonyl group,2,4,6-trimethylphenylsulfonyl group and phenylsulfonyl group.

The nitrogen atom of the indazole ring of the present invention compoundcan be protected with a protective group.

Examples of the protective group for a nitrogen atom of the indazolering are those which have been commonly used as the protective groupsfor a nitrogen atom of the indazole ring including a substituted alkylgroup or an unsubstituted alkenyl group such as benzyl group, tritylgroup, diphenylmethyl group, (4-methoxyphenyl)diphenylmethyl group andallyl group; hydrocarbonyl group is formyl group; a substituted orunsubstituted alkylcarbonyl group, a substituted or unsubstitutedarylcarbonyl group or an unsubstituted heterocyclic carbonyl group suchas trichloroacetyl group, trifluoroacetyl group, acetyl group,4-chlorobenzoyl group, benzoyl group and picolinoyl group; a substitutedor unsubstituted alkyloxycarbonyl group or a substituted orunsubstituted aryloxycarbonyl group such as2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group,diphenylmethoxycarbonyl group, methoxycarbonyl group, isobutoxycarbonylgroup, tert-butoxycarbonyl group, phenoxycarbonyl group and3-nitrophenoxycarbonyl group; and a substituted or unsubstitutedalkylsulfonyl group or a substituted or unsubstituted arylsulfonyl groupsuch as benzylsulfonyl group, tolylsulfonyl group, methylsulfonyl group,4-chlorophenylsulfonyl group, 2,4,6-trimethylphenylsulfonyl group andphenylsulfonyl group.

With regard to a “salt” in the present invention compound, there is noparticular limitation so far as it is a pharmaceutically acceptable saltand its examples are a salt with inorganic acid such as hydrochloricacid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid andphosphoric acid; a salt with organic acid such as acetic acid, fumaricacid, maleic acid, succinic acid, citric acid, tartaric acid, adipicacid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid,p-toluenesulfonic acid and trifluoroacetic acid; a salt with alkalimetal such as lithium, sodium and potassium; a salt with alkali earthmetal such as calcium and magnesium; and a quaternary salt with ammoniaand methyl iodide.

In the “plural groups” in the present invention, such groups can be thesame or different. Incidentally, halogen atom, hydrogen atom andmonocyclic heterocycle are also covered within a “group”.

When there are geometrical isomers such as a syn-anti isomer and anoptical isomer in the present invention compound, such an isomer is alsowithin the scope of the present invention.

The present invention compound can be also in a form of a hydrate or asolvate.

Preferred examples of the present invention compound defined as above inthe formula [I] are compounds where the aforementioned substitutedalkoxy group, substituted alkyl group, substituted alkenyl group and/orsubstituted aryl group are (is) those (that) substituted with one ormore group(s) selected from the group consisting of halogen atom,hydroxyl group, an unsubstituted alkoxy group, an unsubstituted arylgroup, hydroxyimino group and an unsubstituted alkoxyimino group, or asalt thereof.

Other preferred examples of the present invention compound defined asabove in the formula [I] are the compounds which are defined by one ormore combination(s) of those chosen from the following six choices of i)to vi) or a salt thereof.

i) a ring X is benzene ring or pyridine ring;

ii) R¹ and R² are hydrogen atom or alkyl group;

iii) R¹ and R² are bonded to form an unsubstituted cycloalkane ring;

iv) R³ is hydrogen atom, a substituted alkyl group, an unsubstitutedalkenyl group, carboxyl group or an ester or an amide thereof, aminogroup or cyano group;

v) R⁴ is hydrogen atom, hydroxyl group, a substituted or unsubstitutedalkoxy group, an unsubstituted alkenyloxy group, an unsubstitutedcycloalkyloxy group, a substituted or unsubstituted alkyl group, anunsubstituted alkenyl group, an unsubstituted cycloalkyl group, aminogroup, an unsubstituted alkylamino group, nitro group, cyano group or amonocyclic heterocycle group; and

vi) R⁵ is halogen atom or hydrogen atom.

Preferred examples of the formula [I] among the above are as follows.

i) a ring X is benzene ring or pyridine ring;

ii) R¹ and R² are hydrogen atom or alkyl group;

iii) R¹ and R² can be bonded to form an unsubstituted cycloalkane ring;

iv) R³ is hydrogen atom, a substituted alkyl group, an unsubstitutedalkenyl group, carboxyl group or an ester or an amide thereof, aminogroup or cyano group;

v) R⁴ is hydrogen atom, hydroxyl group, a substituted or unsubstitutedalkoxy group, an unsubstituted alkenyloxy group, an unsubstitutedcycloalkyloxy group, a substituted or unsubstituted alkyl group, anunsubstituted alkenyl group, an unsubstituted cycloalkyl group, aminogroup, an unsubstituted alkylamino group, nitro group, cyano group or amonocyclic heterocycle group; and

vi) R⁵ is halogen atom or hydrogen atom.

In the present invention compound defined as above in the formula [I],other preferred examples are compounds where the substituted alkoxygroup is that substituted with halogen atom and/or the substituted alkylgroup is that substituted with one or more group(s) selected from thegroup consisting of hydroxyl group and hydroxyimino group, or a saltthereof.

More preferred examples of the present invention compound defined asabove in the formula [I] are the compounds which are defined by one ormore combination(s) of those chosen from the following six choices of i)to vi) or a salt thereof.

i) a ring X is benzene ring or pyridine ring;

ii) R¹ and R² are hydrogen atom, methyl group or ethyl group;

iii) R¹ and R² are bonded to form a cyclopentane ring;

iv) R³ is hydrogen atom, hydroxymethyl group, hydroxyiminomethyl group,1-methylvinyl group, carboxyl group, methoxycarbonyl group,aminocarbonyl group, amino group or cyano group;

v) R⁴ is hydrogen atom, hydroxyl group, methoxy group, ethoxy group,n-propyloxy group, n-butyloxy group, isopropyloxy group, difluoromethoxygroup, 2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, allyloxygroup, cyclopropyloxy group, cyclopropylmethyloxy group, ethyl group,vinyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethylgroup, cyclopropyl group, amino group, methylamino group, dimethylaminogroup, diethylamino group, nitro group, cyano group, pyrrolidine ring,pyrrole ring, pyrazole ring, oxazole ring, isoxazole ring, piperidinering, pyridine ring or morpholine ring; and

vi) R⁵ is chlorine atom or hydrogen atom.

The particularly preferred examples in the formula [I] are the followingcompounds in the formula [I] or a salt thereof.

i) a ring X is benzene ring or pyridine ring;

ii) R¹ and R² are hydrogen atom, methyl group or ethyl group;

iii) R¹ and R² can be bonded to form a cyclopentane ring;

iv) R³ is hydrogen atom, hydroxymethyl group, hydroxyiminomethyl group,1-methylvinyl group, carboxyl group, methoxycarbonyl group,aminocarbonyl group, amino group or cyano group;

v) R⁴ is hydrogen atom, hydroxyl group, methoxy group, ethoxy group,n-propyloxy group, n-butyloxy group, isopropyloxy group, difluoromethoxygroup, 2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, allyloxygroup, cyclopropyloxy group, cyclopropylmethyloxy group, ethyl group,vinyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethylgroup, cyclopropyl group, amino group, methylamino group, dimethylaminogroup, diethylamino group, nitro group, cyano group, pyrrolidine ring,pyrrole ring, pyrazole ring, oxazole ring, isoxazole ring, piperidinering, pyridine ring or morpholine ring; and

vi) R⁵ is chlorine atom or hydrogen atom.

As mentioned hereinabove already, the present invention compound has thechemical structural characteristic as shown in the following 1) to 4)and, in addition, each of such chemical structural characteristics of 1)to 4) and/or a combination thereof are/is very important in exhibitingthe inhibiting action of the present invention compound for Rho kinase.

1) An indazole ring is a main skeleton.

2) A ring X is directly bonded to an indazole ring.

3) A ring X has an amino-substituted alkyl group or cycloalkyl group.

4) In the above 3), the amino group is located at 1-position of thealkyl group or the cycloalkyl group.

In particular, in addition to those 1) to 4), the present inventioncompound in which

5) the carbon atom in which the amino group of the above 3) isintroduced is not an asymmetric carbon atom

exhibits a particularly good Rho kinase inhibiting action and thepresent invention compound having those chemical structure is morepreferred.

Further, the present invention compound in which a ring X is directlybonded to the 5-position of the indazole ring exhibits much more Rhokinase inhibiting action and the present invention compound where thering X is located at that position is still more preferred.

Incidentally, the present invention compound in which the alkyl group orthe cycloalkyl group which is substituted with an amino group asmentioned in the above 3) is

a) bonded to 4-position of a benzene ring when the ring X is benzene and

b) bonded to 5-position of a pyridine ring when the ring X is a pyridinering

exhibits far more Rho kinase inhibiting action and the present inventioncompound where the ring X is located at such that position isparticularly preferred.

The particularly preferred examples of the present invention compoundare the compounds which will be shown below or a salt thereof.Incidentally, in the chemical structural formulae, Me is methyl group,Et is ethyl group, Bn is benzyl group and Ac is acetyl group unlessotherwise mentioned.5-[4-(1-Amino-1-methylethyl)phenyl]-1H-indazole

1-Acetyl-5-[4-(1-amino-methylethyl)phenyl]-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-nitro-1H-indazole

4-Amino-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-benzylamino-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-methylamino-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-3-methoxycarbonyl-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-3-carboxy-1H-indazole

3-Aminocarbonyl-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole

3-Amino-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-3-hydroxyiminomethyl-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-3-cyano-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-3-hydroxymethyl-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-3-(1-methylvinyl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-dimethylamino-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-nitro-1H-indazole

4-(N-Acetylamino)-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole

5-[4-(Aminomethyl)phenyl]-4-nitro-1H-indazole

4-Amino-5-[4-(aminomethyl)phenyl]-1H-indazole

4-Amino-5-[4-(1-aminocyclopentyl)phenyl]-1H-indazole

4-Amino-5-[4-(1-amino-1-ethylpropyl)phenyl]-1H-indazole

5-[4-(Aminomethyl)phenyl]-4-dimethylamino-1H-indazole

5-[4-(1-Aminocyclopentyl)phenyl]-4-dimethylamino-1H-indazole

5-[4-(1-Amino-1-ethylpropyl)phenyl]-4-dimethylamino-1H-indazole

5-[4-(1-Aminoethyl)phenyl]-4-dimethylamino-1H-indazole

5-[5-(1-Amino-1-methylethyl)-3-chloropyridin-2-yl]-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-ethyl-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-y1]-4-cyclopropyl-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-vinyl-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-diethylamino-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(2-hydroxyethyl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)pyridin-2-yl]-4-(2-hydroxy-ethyl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(1-hydroxyethyl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-hydroxymethyl-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-cyano-1H-indazole

6-[4-(1-Amino-1-methylethyl)phenyl]-1H-indazole

1-Acetyl-6-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrrol-1-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-isopropoxy-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(piperidin-1-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrrolidin-1-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(morpholin-4-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-methoxy-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-methoxy-1H-indazole

5-[5-(1-Aminocyclopentyl)pyridin-2-yl]-4-methoxy-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-ethoxy-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-hydroxy-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-ethoxy-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-isopropoxy-1H-indazole

5-[5-(1-Amino-1-ethylpropyl)pyridin-2-yl]-4-methoxy-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-n-propoxy-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-difluoromethoxy-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(2,2,2-trifluoroethoxy)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-n-butoxy-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(2-fluoroethoxy)-1H-indazole

4-Allyloxy-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-n-propoxy-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-difluoromethoxy-1H-indazole

5-[5-(1-Amino-1-ethylpropyl)pyridin-2-yl]-4-ethoxy-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyridin-4-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyridin-3-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyridin-2-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrazol-4-yl)-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-(pyrazol-4-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(oxazol-5-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrazol-3-yl)-1H-indazole

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(isoxazol-5-yl)-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-hydroxy-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-cyclopropyloxy-1H-indazole

5-[5-(1-Amino-1-ethylpropyl)pyridin-2-yl]-4-cyclopropyloxy-1H-indazole

5-[4-(1-Amino-1-ethylpropyl)phenyl]-4-difluoromethoxy-1H-indazole

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-cyclopropylmethyloxy-1H-indazole

Representative process for the production of the present inventioncompound will be shown below. Incidentally, specific process for theproduction of each of the present invention compounds will beillustrated in detail under the item of “Production Examples” in theExamples which will be mentioned later.

Synthetic pathway 1 or synthetic pathway 2: The compound A is subjectedto a coupling reaction with the compound B, or the compound C issubjected to a coupling reaction with the compound D, in an organicsolvent in the presence of a metal catalyst and/or a base catalystwhereupon the present invention compound is able to be produced.

When a protective group is used for the convenience of the production inthe aforementioned production process, the protective group is able tobe eliminated by a commonly used method after the reaction.

With regard to the substituent(s) on the ring X and/or the indazolering, desired substituent(s) may be introduced in its initial stage orit is also acceptable that, after the fundamental skeleton ismanufactured by the aforementioned method, the desired substituent(s)may be introduced into the fundamental skeleton using oxidation,reduction, alkylation, esterification, amidation, oximation, dehydratingreaction, deprotecting reaction, acetylation, hydrolysis, triflating,coupling reaction, cyclization reaction and/or a commonly used syntheticmethod in which the aforementioned reactions are combined.

With regard to a process for the production of synthetic intermediatesfor the present invention compound, that will be illustrated in detailunder the item of “Production Examples” in the Examples which will bementioned later.

In order to find the utility of the present invention compound, a Rhokinase inhibiting activity of the present invention compound wasevaluated. The details thereof will be illustrated under the item of“Pharmacological Test (Test for Evaluation of Rho Kinase InhibitingActivity)” in the Examples which will be mentioned later. The evaluationof the Rho kinase inhibiting activity of the present invention compoundwas carried out in accordance with the methods mentioned in J. Biol.Chem., 274, 32418 (1999) by Kaibuchi, et al. and mentioned in theinstruction manual for use attached to the commercially availableactivated ROCK II [Upstate Biotechnology, Catalog No. 14-338 (5 units/50μl)]. As a result, the present invention compound was found to have anexcellent Rho kinase inhibiting action and to be very useful as atreating agent for diseases in which Rho kinase is involved.

Further, in order to check the application of the present inventioncompound to specific diseases in which Rho kinase is involved, anintraocular pressure-reducing action of the present invention compoundwas also studied. The details thereof will be illustrated under the itemof “Pharmacological Test (Test for Measurement of Intraocular PressureReduction)” in the Examples which will be mentioned later. It was foundthat, when the present invention compound was topically administered tothe eye of cynomolgus monkey (Macaca fascicularis) (sex: male; one groupcomprising 2 to 6 monkeys), the present invention compound exhibited anexcellent intraocular pressure-reducing action and is useful as atreating agent for eye diseases such as glaucoma as well.

As mentioned already, Rho kinase has been known to deeply participate indiseases such as hypertension, angina pectoris, asthma, peripheralcircular disorder, premature delivery, arteriosclerosis, cancer,inflammatory diseases, autoimmune diseases, AIDS, fertilization andimplantation of fertilized egg, osteoporosis, cerebral functiondisturbance, gastrointestinal dysfunction by bacteria, glaucoma andretinopathy. Accordingly, the present invention compound is very muchexpected as a treating agent for diseases in which Rho kinase isinvolved.

A Rho kinase inhibitor in the present invention means a compound whichinhibits a serine/threonine kinase which is activated as a result ofactivation of Rho.

Examples of glaucoma in the present invention are primary open angleglaucoma, normal tension glaucoma, hypersecretion glaucoma, ocularhypertension, acute angle-closure glaucoma, chronic angle-closureglaucoma, combined mechanism glaucoma, steroid glaucoma, amyloidglaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucomaand plateau iris syndrome.

The present invention compound is able to be administered either orallyor parenterally. Examples of the dosage form are tablets, capsules,granules, powders, injections and eye drops and they are able to be madeinto the pharmaceutical preparations by combining the commonly knowntechniques.

For example, preparations for oral use such as tablets, capsules,granules and powders are able to be prepared by combining the presentinvention compound together, if necessary, with excipient such aslactose, mannitol, starch, crystalline cellulose, light anhydroussilicic acid, calcium carbonate and calcium hydrogen phosphate;lubricant such as stearic acid, magnesium stearate and talc; binder suchas starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose andpolyvinylpyrrolidone; disintegrating agent such as carboxymethylcellulose, lowly substituted hydroxypropyl methylcellulose and calciumcitrate; coating agent such as hydroxypropyl methylcellulose, macrogoland silicone resin; stabilizer such as ethyl p-hydroxybenzoate andbenzyl alcohol; and corrigent such as sweetener, sour agent and flavor.

Parenteral preparations such as injections and eye drops are able to beprepared by combining the present invention compound together, ifnecessary, with isotonicity agent such as glycerol, propylene glycol,sodium chloride, potassium chloride, sorbitol and mannitol; buffer suchas phosphoric acid, phosphate, citric acid, glacial acetic acid,ε-aminocaproic acid and trometamol; pH adjusting agent such ashydrochloric acid, citric acid, phosphoric acid, glacial acetic acid,sodium hydroxide, potassium hydroxide, sodium carbonate and sodiumhydrogen carbonate; solubilizing or dispersing agent such as polysorbate80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, purifiedsoybean lecithin and polyoxyethylene (160) polyoxypropylene (30) glycol;polymer of a cellulose type such as hydroxypropyl methylcellulose andhydroxypropyl cellulose; thickener such as polyvinyl alcohol andpolyvinylpyrrolidone; stabilizer such as edetic acid and sodium edetate;commonly used preservative or antiseptic such as sorbic acid, potassiumsorbate, benzalkonium chloride, benzethonium chloride, methylp-hydroxybenzoate, propyl p-hydroxybenzoate and chlorobutanol; andsoothing agent such as chlorobutanol, benzyl alcohol and lidocaine.

In the case of injections and eye drops, it is desired that pH isadjusted to 4.0 to 8.0 and that osmotic pressure ratio is adjusted toabout 1.0.

Dose of the present invention compound is able to be appropriatelyselected depending upon symptom, age, dosage form, etc. For example, inthe case of oral preparations, usually 0.01 to 1,000 mg per day,preferably 1 to 100 mg per day is able to be administered once daily orby dividing into several times a day. In the case of eye drops, usuallythose having a concentration of 0.0001% to 10% (w/v), preferably 0.01%to 5% (w/v) is able to be administered once daily or by dividing intoseveral times a day.

Production examples of the present invention compounds (Examples 1 to31) and synthetic intermediates (Referential Examples 1 to 48),pharmaceutical preparation examples and results of pharmacological testare shown as hereunder. Incidentally, those examples are for betterunderstanding of the present invention and are not intended to limit thescope of the present invention. Rf values in the physical property inExamples stand for the data measured by a thin-layer chromatography(using TLC Plate Silica Gel 60 F₂₅₄ (trade name) manufactured by Merck)and, in the chemical structural formulae, Me stands for methyl group, Bnstands for benzyl group, Ac stands for acetyl group, Boc stands fortert-butoxycarbonyl group, Tf stands for trifluoromethanesulfonyl group,TBS stands for tert-butyldimethylsilyl group and THP stands fortetrahydropyranyl group unless otherwise mentioned.

PRODUCTION EXAMPLES Referential Example 1 Synthesis of1-bromo-4-(1-cyano-1-methylethyl)benzene (referential compound 1-1)

Sodium hydride (a 60% dispersion in mineral oil) (45 g, 1,100 mmol) wasdividedly added at 0° C., in an argon stream with stirring, to asolution of 100 g (510 mmol) of 4-bromophenylacetonitrile in 1,500 ml ofN,N-dimethylformamide. Then 95 ml (1,500 mmol) of methyl iodide wasdropped thereinto at 0° C. with stirring followed by stirring at 10° C.for 1 hour.

After the reaction was finished, the reaction solution was slowly addedto 900 g of a saturated aqueous solution of ammonium chloride, then 500ml of water was added thereto and the mixture was extracted with 2,000ml of ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium chloride, dried over anhydrous sodium sulfateand concentrated in vacuo to give 110 g of the title compound as a darkbrown oily substance. (Yield: 96%).

Rf value: 0.78 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 224, 226 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.71 (s, 6H),7.32-7.38 (m, 2H), 7.49-7.54 (m, 2H)

As hereunder, the referential compounds 1-2 to 1-7 were produced inaccordance with the production process for the referential compound 1-1.

1-Bromo-4-(1-cyano-1-ethylpropyl)benzene (referential compound 1-2)

Property: light orange oily substance Rf value: 0.64 (n-hexane:ethylacetate=4:1 (v/v)) Mass spectrum (CI, m/z): 252, 254 (M⁺+1) ¹H-NMRspectrum (CDCl₃, δ ppm): 0.91 (dd, J1=7.2 Hz, J2=7.2 Hz, 6H), 1.87 (dq,J1=14.3 Hz, J2=7.2 Hz, 2H), 2.04 (dq, J1=14.3 Hz, J2=7.2 Hz, 2H),7.21-7.28 (m, 2H), 7.48-7.55 (m, 2H)

1-Bromo-4-(1-cyanocyclopentyl)benzene (referential compound 1-3)

Property: brown oily substance Rf value: 0.50 (n-hexane:ethylacetate=4:1 (v/v)) Mass spectrum (EI, m/z): 249, 251 (M⁺) ¹H-NMRspectrum (CDCl₃, δ ppm): 1.90-2.10 (m, 6H), 2.40-2.55 (m, 2H), 7.30-7.36(m, 2H), 7.45-7.55 (m, 2H)

2-Bromo-5-(1-cyano-1-methylethyl)pyridine (referential compound 1-4)

Rf value: 0.32 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 225, 227 (M⁺+1) IR spectrum (KBr, cm⁻¹): 2243 ¹H-NMR spectrum(CDCl₃, δ ppm): 1.76 (s, 6H), 7.52 (d, J=8.3 Hz, 1H), 7.67 (dd, J1=8.3Hz, J2=2.7 Hz, 1H), 8.50 (d, J=2.7 Hz, 1H)

5-(1-Cyano-1-methylethyl)-2,3-dichloropyridine (referential compound1-5)

IR spectrum (KBr, cm⁻¹): 2239 Mass spectrum (CI, m/z): 215 (M⁺+1) ¹H-NMRspectrum (CDCl₃, δ ppm): 1.77 (s, 6H), 7.88 (d, J=2.4 Hz, 1H), 8.43 (d,J=2.4 Hz, 1H)

2-Bromo-5-(1-cyanocyclopentyl)pyridine (referential compound 1-6)

Property: colorless oily substance Rf value: 0.60 (n-hexane:ethylacetate=1:1 (v/v)) Mass spectrum (CI, m/z): 251, 253 (M⁺+1) ¹H-NMRspectrum (CDCl₃, δ ppm): 1.90-2.20 (m, 6H), 2.40-2.60 (m, 2H), 7.51 (dd,J1=8.3 Hz, J2=0.7 Hz, 1H), 7.64 (dd, J=8.3 Hz, J2=2.7 Hz, 1H), 8.47 (dd,J1=2.7 Hz, J2=0.7 Hz, 1H)

2-Bromo-5-(1-cyano-1-ethylpropyl)pyridine (referential compound 1-7)

Rf value: 0.85 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 253, 255 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.95 (dd, J1=7.3Hz, J2=7.3 Hz, 6H), 1.91 (dq, J1=14.2 Hz, J2=7.3 Hz, 2H), 2.12 (dq,J1=14.2 Hz, J2=7.3 Hz, 2H), 7.52 (dd, J1=8.4 Hz, J2=0.8 Hz, 1H), 7.59(dd, J1=8.4 Hz, J2=2.7 Hz, 1H), 8.42 (dd, J1=2.7 Hz, J2=0.8 Hz, 1H)

Referential Example 2 Synthesis of4-(1-aminocarbonyl-1-methylethyl)-1-bromobenzene (referential compound2-1)

Potassium trimethylsilanolate (purity: 90%) (250 g, 1,800 mmol) wasadded at room temperature to a solution of 100 g (450 mmol) of1-bromo-4-(1-cyano-1-methylethyl)benzene (referential compound 1-1) in1,000 ml of toluene with stirring in an argon stream and the mixture wasstirred for 4.5 hours under a condition of heating to reflux. After thereaction was finished, the reaction solution was cooled down to roomtemperature and 500 ml of water was dropped thereinto. The mixedsolution was stirred for 25 minutes at room temperature and theresulting solid was filtered off and washed with 400 ml of water to give99 g of the title compound as white powder (yield: 92%).

Melting point: 139 to 141° C. Rf value: 0.23 (n-hexane:ethyl acetate=1:1(v/v)) Mass spectrum (CI, m/z): 242, 244 (M⁺+1) ¹H-NMR spectrum (CDCl₃,δ ppm): 1.56 (s, 6H), 5.18 (brs, 1H), 5.52 (brs, 1H), 7.25-7.30 (m, 2H),7.46-7.51 (m, 2H)

Hereinafter, referential compounds 2-2 to 2-3 were produced inaccordance with the production process for the referential compound 2-1.

4-(1-Aminocarbonyl-1-ethylpropyl)-1-bromobenzene (referential compound2-2)

Property: white powder Rf value: 0.42 (n-hexane:ethyl acetate=1:1 (v/v))Mass spectrum (CI, m/z): 270, 272 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm):0.76 (dd, J1=7.4 Hz, J2 7.4 Hz, 6H), 1.98 (q, J=7.4 Hz, 2H), 1.99 (q,J=7.4 Hz, 2H), 5.04-5.36 (m, 2H), 7.18-7.24 (m, 2H), 7.45-7.51 (m, 2H)

4-(1-Aminocarbonylcyclopentyl)-1-bromobenzene (referential compound 2-3)

Property: orange powder Melting point: 154 to 155° C. Rf value: 0.20(n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum. (CI, m/z): 268, 270(M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.50-2.13 (m, 6H), 2.40-2.55 (m,2H), 4.95-5.35 (m, 2H), 7.20-7.30 (m, 2H), 7.45-7.55 (m, 2H)

Referential Example 3 Synthesis of5-(1-aminocarbonyl-1-methylethyl)-2-bromopyridine (referential compound3-1)

A 35% aqueous solution of hydrogen peroxide (9.60 ml, 93.3 mmol) and1.86 g (13.5 mmol) of potassium carbonate were added, at 0° C., to asolution of 1.50 g (6.66 mmol) of2-bromo-5-(1-cyano-1-methylethyl)pyridine (referential compound 1-4) in15 ml of dimethyl sulfoxide and the mixture was stirred for 15 minutes.After that, a cooling bath was removed and the mixture was stirred on awater bath for 2 hours.

After the reaction was finished, the reaction solution was poured into200 ml of water and the mixture was extracted with 500 ml of1,2-dichloroethane. The organic layer was successively washed with waterand a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated in vacuo to give 1.63 g ofthe title compound as white powder (yield: quantitative).

Rf value: 0.17 (n-hexane:ethyl aetate=1:1 (v/v)) Mass spectrum (CI,m/z): 243, 245 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.61 (s, 6H), 5.36(brs, 2H), 7.47 (dd, J1=8.3 Hz, J2=0.7 Hz, 1H), 7.59 (dd, J1=8.3 Hz,J2=2.7 Hz, 1H), 8.42 (dd, J1=2.7 Hz, J2=0.7 Hz, 1H)

As hereunder, the referential compound 3-2 was produced in accordancewith the production process for the referential compound 3-1.

5-(1-Aminocarbonyl-1-methylethyl)-2,3-dichloropyridine (referentialcompound 3-2)

Rf value: 0.38 (chloroform:methanol=97:3 (v/v)) Mass spectrum (CI, m/z):233 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.62 (s, 6H), 5.50 (brs, 2H),7.81 (d, J=2.2 Hz, 1H), 8.34 (d, J=2.2 Hz, 1H)

Referential Example 4 Synthesis of1-bromo-4-(1-tert-butoxycarbonylamino-1-methylethyl)benzene (referentialcompound 4-1)

In an argon stream, 260 g (600 mmol) of[bis(trifluoroacetoxy)iodo]benzene was added, at room temperature withstirring, to a solution of 99 g (410 mmol) of4-(1-aminocarbonyl-1-methylethyl)-1-bromobenzene (referential compound2-1) in 1,000 ml of tert-butanol and the mixture was stirred for 30minutes under a condition of heating to reflux. After that, 100 ml(1,200 mmol) of pyridine was added thereto and the mixture was stirredfor 1 hour under the condition of heating to reflux.

After the reaction was finished, the reaction solution was concentratedin vacuo, 500 g of a 10 weight % aqueous solution of citric acid wasadded to the resulting residue and the mixture was extracted with 2,000ml of toluene. The organic layer was successively washed with asaturated aqueous solution of sodium hydrogen carbonate and a saturatedaqueous solution of sodium chloride, dried over anhydrous sodium sulfateand concentrated in vacuo. n-Hexane (200 ml) was added to the resultingresidue and the resulting solid was filtered off and washed with 400 mlof cold n-hexane to give 77 g of the title compound as light brownpowder (yield: 60%).

Melting point: 92 to 93° C. Rf value: 0.56 (n-hexane:ethyl acetate=4:1(v/v)) Mass spectrum (EI, m/z): 313, 315 (M⁺) ¹H-NMR spectrum (CDCl₃, δppm): 1.36 (brs, 9H), 1.59 (s, 6H), 4.90 (brs, 1H), 7.24-7.29 (m, 2H),7.39-7.45 (m, 2H)

As hereunder, the referential compounds 4-2 to 4-7 were produced inaccordance with the production process for the referential compound 4-1.

1-Bromo-4-(1-tert-butoxycarbonylamino-1-ethylpropyl)benzene (referentialcompound 4-2)

Property: white powder Melting point: 88 to 91° C. Rf value: 0.61(n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI, m/z): 342, 344(M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.74 (dd, J1=7.3 Hz, J2=7.3 Hz,6H), 1.39 (brs, 9H), 1.75-2.10 (m, 4H), 4.73 (brs, 1H), 7.17-7.23 (m,2H), 7.40-7.46 (m, 2H)

1-Bromo-4-(1-tert-butoxycarbonylaminocyclopentyl)benzene (referentialcompound 4-3)

Property: dark brown powder Melting point: 112 to 113° C. Rf value: 0.50(n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (EI, m/z): 339, 341(M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.35 (brs, 9H), 1.70-2.35 (m, 8H),4.86 (brs, 1H), 7.20-7.30 (m, 2H), 7.35-7.45 (m, 2H)

2-Bromo-5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridine(referential compound 4-4)

Melting point: 100 to 103° C. Rf value: 0.53 (n-hexane:ethyl acetate=2:1(v/v)) Mass spectrum (CI, m/z): 315, 317 (M⁺+1) ¹H-NMR spectrum (CDCl₃,δ ppm): 1.37 (brs, 9H), 1.61 (s, 6H), 4.95 (brs, 1H), 7.41 (dd, J1=8.3Hz, J2=0.7 Hz, 1H), 7.56 (dd, J1=8.3 Hz, J2=2.7 Hz, 1H), 8.40 (dd,J1=2.7 Hz, J2=0.7 Hz, 1H)

5-(1-tert-Butoxycarbonylamino-1-methylethyl)-2,3-dichoropyridine(referential compound 4-5)

Rf value: 0.86 (n-hexane:ethyl acetate=3:2 (v/v)) Mass spectrum (CI,m/z): 305 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (brs, 9H), 1.62(s, 6H), 4.95 (brs, 1H), 7.76 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H)

2-Bromo-5-(1-tert-butoxycarbonylaminocyclopentyl)pyridine (referentialcompound 4-6)

Property: white powder Melting point: 123 to 124° C. Rf value: 0.30(n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI, m/z): 341, 343(M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.35 (brs, 9H), 1.70-2.40 (m,8H), 4.89 (brs, 1H), 7.41 (dd, J1=8.3 Hz, J2=0.7 Hz, 1H), 7.58 (dd,J1=8.3 Hz, J2=2.7 Hz, 1H), 8.40 (dd, J1=2.7 Hz, J2=0.7 Hz, 1H)

2-Bromo-5-(1-tert-butoxycarbonylamino-1-ethylpropyl)pyridine(referential compound 4-7)

Rf value: 0.25 (n-hexane:ethyl acetate=1:4 (v/v)) Mass spectrum (CI,m/z): 343, 345 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.78 (dd, J1=7.4Hz, J2=7.4 Hz, 6H), 1.38 (brs, 9H), 1.75-1.90 (m, 2H), 1.95-2.15 (m,2H), 4.74 (brs, 1H), 7.41 (dd, J1=8.3 Hz, J2=0.7 Hz, 1H), 7.50 (dd,J1=8.3 Hz, J2=2.7 Hz, 1H), 8.34 (dd, J1=2.7 Hz, J2=0.7 Hz, 1H)

Referential Example 5 Synthesis of1-bromo-4-(1-tert-butoxycarbonylaminoethyl)benzene (referential compound5)

Triethylamine (2.09 ml) was added to a solution of 2.00 g (10.0 mmol)-of 4-(1-aminoethyl)-1-bromobenzene in 22.3 ml of dichloromethane, themixture was cooled on an ice bath and 2.87 ml (12.0 mmol) ofdi-tert-butyl dicarbonate was added thereto in an argon stream withstirring. After that, temperature of the mixture was raised up to roomtemperature and stirring was conducted for 1 hour.

After the reaction was finished, the reaction solution was poured into200 ml of water and the mixture was extracted with 200 ml of chloroform.The organic layer was successively washed with water, a saturatedaqueous solution of sodium hydrogen carbonate and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting powder was washed twice with each10 ml of hexane to give 2.71 g of the title compound as white powder(yield: 90%).

Rf value: 0.55 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (FAB,m/z): 300, 302 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.27 (d, J=6.8Hz, 3H), 1.36 (brs, 9H), 4.51-4.64 (m, 1H), 7.25 (d, J=8.3 Hz, 2H),7.35-7.45 (m, 1H), 7.49 (d, J=8.3 Hz, 2H)

Referential Example 6 Synthesis of4-(1-tert-butoxycarbonylamino-1-methylethyl)-1-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)benzene(referential compound 6-1)

A 0.95M sec-butyl lithium/n-hexane solution (370 ml, 350 mmol) wasdropped, in an argon stream with stirring at −78° C., into a solution of50 g (160 mmol) of1-bromo-4-(1-tert-butoxycarbonylamino-1-methylethyl)benzene (referentialcompound 4-1) in 800 ml of diethyl ether and the mixture was stirred for30 minutes. After that, 97 ml (480 mmol) of2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane was droppedthereinto at −78° C. and the mixture was stirred at −50° C. for 2 hours.

After the reaction was finished, 300 g of a saturated aqueous solutionof ammonium chloride and then 450 ml of water were successively addedthereto and the mixture was separated into layers. An aqueous layer wasextracted with 300 ml of ethyl acetate again and the organic layers werecombined, washed with a saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate and concentrated in vacuo. n-Hexane(100 ml) was added to the resulting residue and the resulting solid wasfiltered off and successively washed with 100 ml of a mixed solvent(n-hexane:ethyl acetate=4:1 (v/v)) and 100 ml of n-hexane to give 33 gof the title compound as white powder (yield: 58%).

Melting point: 142 to 144° C. Rf value: 0.38 (n-hexane:ethyl acetate=4:1(v/v)) Mass spectrum (CI, m/z): 362 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δppm): 1.10-1.50 (m, 21H), 1.61 (s, 6H), 4.93 (brs, 1H), 7.37-7.42 (m,2H), 7.74-7.79 (m, 2H)

As hereunder, the referential compound 6-2 was produced in accordancewith the production process for the referential compound 6-1.

4-(1-tert-Butoxycarbonylamino-1-ethylpropyl)-1-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)benzene(referential compound 6-2)

Property: white powder Melting point: 141 to 144° C. Rf value: 0.55(n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI, m/z): 390 (M⁺+1)¹H-NMR spectrum (CDCl₃, δ ppm): 0.73 (t, J=7.3 Hz, 6H), 1.34 (s, 12H),1.38 (brs, 9H), 1.87-2.11 (m, 4H), 4.79 (brs, 1H), 7.29-7.36 (m, 2H),7.73-7.78 (m, 2H)

Referential Example 7 Synthesis of4-(1-tert-butoxycarbonylaminocyclopentyl)-1-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)benzene(referential compound 7-1)

1-Bromo-4-(1-tert-butoxycarbonylaminocyclopentyl)benzene (referentialcompound 4-3) (340 mg, 1.0 mmol) was added to a solution of 294 mg (3.0mmol) of potassium acetate, 41 mg (0.050 mmol) of a 1:1 adduct of1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride withdichloromethane and 279 mg (1.1 mmol) of bis(pinacolato)diboron in 6.0ml of 1,4-dioxane and the mixture was stirred with heating at 90° C. for10 hours.

After the reaction was finished, 50 ml of toluene and 25 ml of waterwere added thereto, the mixture was filtered through Celite (trade name)and the resulting filtrate was extracted with toluene. The organic layerwas dried over anhydrous magnesium sulfate and concentrated in vacuo.The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=6:1 (v/v)), thefraction containing the aimed substance was concentrated in vacuo,n-hexane was added to the concentrate and the resulting solid wasfiltered off to give 156 mg of the title compound-as white powder(yield: 40%).

Melting point: 154 to 155° C. Rf value: 0.40 (n-hexane:ethyl acetate=4:1(v/v)) Mass spectrum (EI, m/z): 387 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm):1.00-1.50 (m, 21H), 1.70-2.30 (m, 8H), 4.87 (brs, 1H), 7.39 (d, J=8.2Hz, 2H), 7.75 (d, J=8.2 Hz, 2H)

As hereunder, the referential compound 7-2 was produced in accordancewith the production process for the referential compound 7-1.

4-(1-tert-Butoxycarbonylamino)ethyl-1-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)benzene(referential compound 7-2)

Rf value: 0.40 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 348 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.24-1.31 (m, 15H),1.35 (brs, 9H), 4.51-4.65 (m, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.35-7.44 (m,1H), 7.61 (d, J=8.1 Hz, 2H)

Referential Example 8 Synthesis of 2-bromo-5-(bromomethyl)pyridine(referential compound 8)

N-Bromosuccinimide (16 g, 91 mmol) and 0.40 g (2.4 mmol) of2,2′-azobis(isobutyronitrile) were added to a solution of 12 g (70 mmol)of 2-bromo-5-methylpyridine in 100 ml of 1,2-dichloroethane and themixture was stirred at 85° C. After 15 minutes, 0.40 g (2.4 mmol) of2,2′-azobis(isobutyronitrile) was added thereto and the mixture wasstirred for 15 minutes.

After the reaction was finished, water was added to the reactionsolution and the organic layer was separated therefrom. The organiclayer was dried over anhydrous magnesium sulfate and concentrated invacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 9:1(v/v)) and the fraction containing the aimed substance was concentratedin vacuo to give 15 g of the title compound as white powder (yield:89%).

Rf value: 0.63 (n-hexane:ethyl acetate=9:1 (v/v)) Mass spectrum (CI,m/z): 250, 252, 254 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 4.42 (s, 2H),7.49 (d, J=8.3 Hz, 1H), 7.61 (dd, J1=8.3 Hz, J2=2.7 Hz, 1H), 8.39 (d,J=2.7 Hz, 1H)

Referential Example 9 Synthesis of 5-chloromethyl-2,3-dichloropyridine(referential compound 9)

Pyridine (1.0 ml, 12 mmol) and 18 ml (250 mmol) of thionyl chloride weregradually added, at 0° C., to a solution of 30 g (168 mmol) of5,6-dichloro-3-pyridinemethanol in 250 ml of chloroform and the mixturewas stirred for 2 hours at room temperature.

After the reaction was finished, the reaction solution was poured into amixed solvent of chloroform and water and potassium carbonate was addedthereto so that pH of an aqueous layer was made alkaline. The organiclayer was separated therefrom and dried over anhydrous sodium sulfateand concentrated in vacuo to give 37 g of the title compound as a lightbrown oily substance (yield: quantitative).

Rf value: 0.80 (n-hexane:ethyl acetate=9:1 (v/v)) Mass spectrum (CI,m/z): 196 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 4.54-4.55 (m, 2H),7.84-7.85 (m, 1H), 8.30-8.31 (m, 1H)

Referential Example 10 Synthesis of 2-bromo-5-(cyanomethyl)pyridine(referential compound 10-1)

Potassium cyanide (7.80 g, 120 mmol) was added to a solution of 15.0 g(60.0 mmol) of 2-bromo-5-bromomethylpyridine(referential compound 8) in150 ml of N,N-dimethylformamide and the mixture was slowly stirred at60° C. for 15 minutes. After that, water was added thereto little bylittle until potassium cyanide was completely dissolved and then themixture was stirred at 60° C. for 15 minutes.

After the reaction was finished, the reaction solution was poured intoethyl acetate/saturated aqueous solution of ammonium chloride and theorganic layer was separated therefrom. The organic layer was dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultingresidue was subjected to a silica gel column chromatography (elutingsolvent: n-hexane:ethyl acetate=9:1 to 7:3 (v/v)) and the fractioncontaining the aimed substance was concentrated in vacuo to give 9.24 gof the title compound as pale yellow powder (yield: 61%).

Rf value: 0.15 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 197, 199 (M⁺+1) IR spectrum (KBr, cm⁻¹): 2253 ¹H-NMR spectrum(CDCl₃, δ ppm): 3.74 (s, 2H), 7.61-7.53 (m, 2H), 8.36-8.35 (m, 1H)

As hereunder, referential compound 10-2 was produced in accordance withthe production process for the referential compound 10-1.

5-Cyanomethyl-2,3-dichloropyridine (referential compound 10-2)

Mass spectrum (CI, m/z): 187 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm):3.77-3.78 (m, 2H), 7.82-7.84 (m, 1H), 8.27-8.29 (m, 1H)

Referential Example 11 Synthesis of 5-iodo-1H-indazole (referentialcompound 11-1)

At 0° C., 95 ml (570 mmol) of 6N hydrochloric acid was dropped into asolution of 25.0 g (188 mmol) of 5-amino-1H-indazole in 320 ml ofN,N-dimethylformamide and the mixture was stirred for 20 minutes. Afterthat, a solution of 13.6 g (197 mmol) of sodium nitrite in 75 ml ofwater was dropped thereinto keeping the temperature of the reactionsolution at below 10° C. throughout. After stirring for 30 minutes, 32.8g (198 mmol) of potassium iodide was divisionally added thereto, then acooling bath was removed to warm up the mixture gradually to roomtemperature.

After the reaction was finished, the reaction solution was poured into1,000 ml of water and the mixture was neutralized with an aqueoussolution of sodium hydroxide and extracted with 1,500 ml of toluene andthen with each 500 ml of the same twice. The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultingresidue was subjected to a silica gel column chromatography (elutingsolvent: n-hexane:ethyl acetate=2:1 (v/v)) and the fraction containingthe aimed substance was concentrated in vacuo. Ethyl acetate (50 ml) wasadded to the resulting crude crystals, the mixture was heated todissolve it, 300 ml of n-hexane was added thereto and the resultingsolid was filtered off to give 5.80 g of the title compound as whitepowder (yield: 13%).

Rf value: 0.45 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 245 (M⁺+1). ¹H-NMR spectrum (CDCl₃, δ ppm): 7.30 (ddd, J1=8.8 Hz,J2=1.1 Hz, J3=0.7 Hz, 1H), 7.63 (dd, J1=8.8 Hz, J2=1.5 Hz, 1H), 8.01 (d,J=1.1 Hz, 1H), 8.14 (dd, J1=1.5 Hz, J2=0.7 Hz, 1H), 10.17 (brs, 1H)

As hereunder, referential compounds 11-2 to 11-3 were produced inaccordance with the production process for the referential compound11-1.

6-Iodo-1H-indazole (referential compound 11-2)

Rf value: 0.43 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 245 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 7.39 (dd, J1=8.5 Hz,J2=1.3 Hz, 1H), 7.60 (dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 7.94-7.96 (m, 1H),8.08 (d, J=1.0 Hz, 1H), 13.14 (brs, 1H)

4-(2-Hydroxyethyl)-5-iodo-1H-indazole (referential compound 11-3)

Rf value: 0.65 (ethyl acetate) Mass spectrum (CI, m/z): 289 (M⁺+1)¹H-NMR spectrum (DMSO-d₆, δ ppm): 3.14-3.20 (m, 2H), 3.58-3.66 (m, 2H),4.81 (t, J=5.5 Hz, 1H), 7.20 (dd, J1=8.7 Hz, J2=1.0 Hz, 1H), 7.64 (d,J=8.7 Hz, 1H), 8.13 (d, J=1.0 Hz, 1H), 13.15 (brs, 1H)

Referential Example 12 Synthesis of 1-acetyl-5-iodo-1H-indazole(referential compound 12-1)

Acetic acid (10 ml) and 20 ml of acetic anhydride were added to 1.02 g(4.18 mmol) of 5-iodo-1H-indazole (referential compound 11-1) and themixture was stirred at room temperature for 30 minutes.

After the reaction was finished, the reaction solution was poured into300 ml of water and the resulting solid was filtered off to give 1.08 gof the title compound as white powder (yield: 90%).

Rf value: 0.49 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 287 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 2.78 (s, 3H), 7.81 (dd,J1=8.8 Hz, J2=1.6 Hz, 1H), 8.05 (d, J=0.9 Hz, 1H), 8.10 (dd, J1=1.6 Hz,*J2=0.7 Hz, 1H), 8.23 (ddd, J1=8.8 Hz, J2=0.9 Hz, J3=0.7 Hz, 1H)

As hereunder, the referential compounds 12-2 to 12-4 were produced inaccordance with the production process for the referential compound12-1.

1-Acetyl-3-tert-butoxycarbonylamino-5-iodo-1H-indazole (referentialcompound 12-2)

Rf value: 0.31 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 402 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.57 (s, 9H), 2.66 (s,3H), 7.03 (brs, 1H), 7.80 (dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 8.19 (dd,J1=8.8 Hz, J2=0.5 Hz, 1H), 8.46-8.47 (m, 1H)

1-Acetyl-5-iodo-3-(1-methylvinyl)-1H-indazole (referential compound12-3)

Rf value: 0.73 (n-hexane:ethyl acetate=-4:1 (v/v)) Mass spectrum (CI,m/z): 327 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 2.30-(dd, J1=1.3 Hz,J2=0.8 Hz, 3H), 2.75 (s, 3H), 5.59-5.61 (m, 1H), 5.82-5.84 (m, 1H), 7.80(dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 8.23-8.28 (m, 2H)

1-Acetyl-6-iodo-1H-indazole (referential compound 12-4)

Rf value: 0.46 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 287 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 2.78 (s, 3H), 7.46 (dd,J1=8.3 Hz, J2=0.7 Hz, 1H), 7.67 (dd, J1=8.3 Hz, J2=1.3 Hz, 1H), 8.07 (d,J=0.7 Hz, 1H), 8.89-8.90 (m, 1H)

Referential Example 13 Synthesis of 5-iodo-4-nitro-1H-indazole(referential compound 13)

Nitric acid (12.5 ml) was gradually dropped, at 0° C., into a solutionof 1.57 g (6.43 mmol) of 5-iodo-1H-indazole (referential compound 11-1)in 25 ml of concentrated sulfuric acid and the mixture was stirred for 1hour. After that, a cooling bath was removed to warm up the mixturegradually to room temperature.

After the reaction was finished, the reaction solution was graduallypoured into 150 ml of ice water, and the mixture was neutralized with anaqueous solution of sodium hydroxide and extracted with each 300 ml ofethyl acetate for three times. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=3:1 (v/v)) and the fraction containing the aimedsubstance was concentrated in vacuo to give 0.90 g of the title compoundas yellow powder (yield: 48%).

Rf value: 0.32 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 290 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 7.69 (dd, J1=8.8 Hz,J2=1.0 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 8.23 (d, J=1.0 Hz, 1H), 13.88(brs, 1H)

Referential Example 14 Synthesis of1-tert-butoxycarbonyl-5-iodo-4-nitro-1H-indazole (referential compound14-1)

4-Dimethylaminopyridine (38.0 mg, 0.31 mmol) and 18 ml oftetrahydrofuran were added to 898 mg (3.11 mmol) of5-iodo-4-nitro-1H-indazole (referential compound 13). After that, asolution of 1.36 g (6.23 mmol) of di-tert-butyl dicarbonate in 9 ml oftetrahydrofuran was added thereto with stirring in an argon stream andthe mixture was stirred at room temperature for 1 hour.

After the reaction was finished, the reaction solution was concentratedin vacuo, the resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=20:1 (v/v)) andthe fraction containing the aimed substance was concentrated in vacuo togive 1.17 g of the title compound as yellow powder (yield: 97%).

Rf value: 0.33 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 390 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.73 (s, 9H), 8.11 (d,J=8.8 Hz, 1H), 8.19 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 8.40 (d, J=0.7 Hz,1H)

As hereunder, the referential compounds 14-2 to 14-3 were produced inaccordance with the production process for the referential compound14-1.

1-tert-Butoxycarbonyl-5-iodo-3-methoxycarbonyl-1H-indazole (referentialcompound 14-2)

Rf value: 0.51 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 403 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.73 (s, 9H), 4.05 (s,3H), 7.32 (dd, J1=8.9 Hz, J2=1.7 Hz, 1H), 7.99 (dd, J1=8.9 Hz, J2=0.7Hz, 1H), 8.64 (dd, J1=1.7 Hz, J2=0.7 Hz, 1H)

1-tert-Butoxycarbonyl-3-formyl-5-iodo-1H-indazole (referential compound14-3)

Rf value: 0.54 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 373 (M⁺+1) ¹H-NMR spectrum . (CDCl₃, δ ppm): 1.76 (s, 9H), 7.85(dd, J1=9.0 Hz, J2=1.7 Hz, 1H), 7.96 (dd, J1=9.0 Hz, J2=0.7 Hz, 1H),8.71 (dd, J1=1.7 Hz, J2=0.7 Hz, 1H), 10.30 (s, 1H)

Referential Example 15 Synthesis of 5-iodo-3-methoxycarbonyl-1H-indazole(referential compound 15)

A solution of 2.72 g (68.0 mmol) of sodium hydroxide in 120 ml of waterwas added to 17.5 g (64.1 mmol) of 5-iodoisatin and the mixture wasstirred at room temperature for 15 minutes. After that, a solution of4.96 g (71.9 mmol) of sodium nitrite in 20 ml of water was added at 0°C. thereto and a solution of 12.2 g (124 mmol) of concentrated sulfuricacid in 120 ml of water was dropped thereinto keeping the temperature ofthe reaction solution at not higher than 10° C. throughout. Afterstirring for 30 minutes, a solution of 30.8 g (162 mmol) of anhydroustin (II) chloride in 60 ml of concentrated hydrochloric acid was droppedthereinto keeping the temperature of the reaction solution at not higherthan 10° C. throughout. After finishing the dropping, a cooling bath wasremoved to warm up the mixture gradually to room temperature and stirredfor 2 hours and the mixture was stirred for 2 hours.

After that, the resulting solid was filtered off, 300 ml of methanol and1 ml of concentrated sulfuric acid were added to 22.9 g of the resultingcrude crystals and the mixture was heated to reflux with stirring for 10hours.

After the reaction was finished, the reaction solution was filtered andthe filtrate was concentrated in vacuo and poured into 500 ml of water.The mixed solution was neutralized with an aqueous solution of sodiumhydroxide and extracted with 1,000 ml of chloroform. The organic layerwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated in vacuo. Theresulting residue was subjected to a silica gel column chromatography(eluting solvent: n-hexane:ethyl acetate=2:1 (v/v)) and the fractioncontaining the aimed substance was concentrated in vacuo. Ethyl acetate(50 ml) was added to the resulting crude crystals, the mixture washeated to dissolve it, 300 ml of n-hexane was added thereto and theresulting solid was filtered off to give 4.93 g of the title compound asbrown powder (yield: 26%).

Rf value: 0.44 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 303 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 4.06 (s, 3H), 7.38 (dd,J1=8.8 Hz, J2=0.6 Hz, 1H), 7.72 (dd, J1=8.8 Hz, J2=1.5 Hz, 1H), 8.64(dd, J1=1.5 Hz, J2=0.6 Hz, 1H), 10.70 (brs, 1H)

Referential Example 16 Synthesis of 3-carboxy-5-iodo-1H-indazole(referential compound 16)

Tetrahydrofuran (10 ml), 2 ml of methanol and 8 ml of 1N aqueoussolution of sodium hydroxide were added to 328 mg (1.09 mmol) of5-iodo-3-methoxycarbonyl-1H-indazole (referential compound 15) and themixture was stirred at 75° C. for 4 hours.

After the reaction was finished, concentrated hydrochloric acid wasadded to the reaction solution to adjust to pH 1 and the mixture wasconcentrated in vacuo. Water (50 ml) was added to the resulting residueand the resulting solid was filtered off to give 189 mg of the titlecompound as yellow powder (yield: 60%).

Mass spectrum (CI, m/z): 289 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm):7.52 (d, J=8.8 Hz, 1H), 7.68 (dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 8.44 (d,J=1.7 Hz, 1H), 13.11 (brs, 1H), 13.94 (brs, 1H)

Referential Example 17 Synthesis of3-tert-butoxycarbonylamino-5-iodo-1H-indazole (referential compound 17)

A solution of 140 mg (1.4 mmol) of triethylamine in 1 ml of tert-butanoland a solution of 260 mg (0.95 mmol) of diphenyl phosphoryl azide in 1ml of tert-butanol were added to a solution of 180 mg (0.62 mmol) of3-carboxy-5-iodo-1H-indazole (referential compound 16) in 5 ml oftert-butanol with stirring in an argon stream and the mixture was heatedto reflux for 7 hours with stirring.

After the reaction was finished, the reaction solution was poured into50 ml of a saturated aqueous solution of ammonium chloride and themixture was extracted with 100 ml of ethyl acetate. The organic layerwas successively washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and concentratedin vacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=2:1 (v/v)) andthe fraction containing the aimed substance was concentrated in vacuo togive 33 mg of the title compound as yellow powder (yield: 15%).

Rf value: 0.32 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 359 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.54 (s, 9H), 6.91(brs, 1H), 7.16 (dd, J1=8.8 Hz, J2=0.5 Hz, 1H), 7.61 (dd, J1=8.8 Hz,J2=1.7 Hz, 1H), 8.36-8.37 (m, 1H), 9.47 (brs, 1H)

Referential Example 18 Synthesis of 3-hydroxymethyl-5-iodo-1H-indazole(referential compound 18)

A 1M solution (32 ml, 32.0 mmol) of diisobutyl aluminum hydride intoluene was dropped at −78° C. into a solution of 2.41 g (7.89 mmol) of5-iodo-3-methoxycarbonyl-1H-indazole (referential compound 15) in 80 mlof tetrahydrofuran with stirring in an argon stream. The mixture wasstirred at −78° C. for 30 minutes and then stirred at 0° C. for 2.5hours.

After the reaction was finished, a saturated aqueous solution ofammonium chloride was gradually added to the reaction solution at 0° C.,then 300 ml of ethyl acetate was added thereto and the mixture wasfiltered through Celite. The filtrate was dried over anhydrous magnesiumsulfate and concentrated in vacuo to give 2.31 g of the title compoundas yellow powder (yield: quantitative).

Rf value: 0.25 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 275 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 4.75 (d, J=5.8 Hz,2H), 5.26 (t, J=5.8 Hz, 1H), 7.35 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 7.56(dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 8.25 (dd, J1=1.7 Hz, J2=0.7 Hz, 1H),12.93 (brs, 1H)

Referential Example 19 Synthesis of 3-formyl-5-iodo-1H-indazole(referential Compound 19)

Manganese dioxide (6.94 g, 79.8 mmol) was added to a solution of 2.31 g(8.43 mmol) of 3-hydroxymethyl-5-iodo-1H-indazole (referential compound18) in 50 ml of tetrahydrofuran and 50 ml of dichloromethane and themixture was stirred at room temperature for 1 hour.

After the reaction was finished, the reaction solution was filtered andthe filtrate was concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=1:1 (v/v)) and the fraction containing the aimedsubstance was concentrated in vacuo to give 1.84 g of the title compoundas brown powder (yield: 80%).

Rf value: 0.57 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 273 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 7.58 (dd, J1=8.8 Hz,J2=0.7 Hz, 1H), 7.76 (dd, J1=8.8 Hz, J2 1.7 Hz, 1H), 8.49 (dd, J1=1.7Hz, J2=0.7 Hz, 1H), 10.17 (s, 1H), 14.30 (brs, 1H)

Referential Example 20 Synthesis of3-(1-hydroxy-1-methylethyl)-5-iodo-1H-indazole (referential compound 20)

A 0.96M solution (8.1 ml, 7.8 mmol) of methyl magnesium bromide intetrahydrofuran was added at 0° C. to a solution of 300 mg (0.99 mmol)of 5-iodo-3-methoxycarbonyl-1H-indazole (referential compound 15) in 5ml of tetrahydrofuran with stirring in an argon stream and the mixturewas stirred at room temperature for 5 hours.

After the reaction was finished, 50 ml of a saturated aqueous solutionof ammonium chloride was added to the reaction solution at 0° C. and themixture was extracted with 100 ml of ethyl acetate. The organic layerwas successively washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and concentratedin vacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=2:1 (v/v)) andthe fraction containing the aimed substance was concentrated in vacuo togive 220 mg of the title compound as yellow powder (yield: 74%).

Rf value: 0.32 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 303 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.56 (s, 6H), 5.27(s, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.53 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H),8.39 (d, J=1.6 Hz, 1H), 12.77 (brs, 1H)

Referential Example 21 Synthesis of 5-iodo-3-(1-methylvinyl)-1H-indazole(referential compound 21)

A solution (6 ml) of 4N hydrogen chloride/1,4-dioxane was added to 115mg (0.381 mmol) of 3-(1-hydroxy-1-methylethyl)-5-iodo-1H-indazole(referential compound 20) and the mixture was heated to reflux for 4hours with stirring.

After the reaction was finished, the reaction solution was concentratedin vacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=6:1 (v/v)) andthe fraction containing the aimed substance was concentrated in vacuo togive 37.0 mg of the title compound as yellow powder (yield: 34%).

Rf value: 0.37 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 285 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 2.30 (dd, J1=1.5 Hz,J2=1.0 Hz, 3H), 5.41-5.44 (m, 1H), 5.72-5.74 (m, 1H), 7.26 (dd, J1=8.8Hz, J2=0.7 Hz, 1H), 7.63 (dd, J1=8.8 Hz, J2=1.5 Hz, 1H), 8.33 (dd,J1=1.5 Hz, J2=0.7 Hz, 1H), 9.90(brs, 1H)

Referential Example 22 Synthesis of 2-benzyloxy-6-nitrotoluene(referential compound 22-1)

Potassium carbonate (41.5 g, 300 mmol) and 200 ml ofN,N-dimethylformamide were added to 30.6 g (200 mmol) of2-methyl-3-nitrophenol. After that, 23.8 ml (200 mmol) of benzyl bromidewas added thereto with stirring in an argon stream and the mixture wasstirred at room temperature for 3 hours.

After the reaction was finished, the reaction solution was poured into1,000 ml of water and and the mixture was extracted with 800 ml oftoluene and 500 ml of the same for two times. The organic layer wassuccessively washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and concentratedin vacuo to give 49.3 g of the title compound as yellow powder (yield:quantitative).

Rf value: 0.48 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 244 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 2.42 (s, 3H), 5.13 (s,2H), 7.08-7.11 (m, 1H), 7.21-7.27 (m, 1H), 7.32-7.44 (m, 6H)

As hereunder, the referential compounds 22-2 to 22-3 were produced inaccordance with the production process for referential compound 22-1.

2-Ethoxy-6-nitrotoluene (referential compound 22-2)

Rf value: 0.55 (n-hexane:ethyl acetate=5:1 (v/v)) Mass spectrum (CI,m/z): 182 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.46 (t, J=6.9 Hz, 3H),2.37 (s, 3H), 4.08 (q, J=6.9 Hz, 2H), 7.02 (d, J=8.2 Hz, 1H), 7.16-7.23(m, 1H), 7.35-7.42 (m, 1H)

6-Nitro-3-n-propoxytoluene (referential compound 22-3)

Rf value: 0.62 -(n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 196 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.07 (t, J=7.4 Hz, 3H),1.80-1.92 (m, 2H), 2.37 (s, 3H), 3.97 (t, J=6.3 Hz, 2H), 7.02 (d, J=7.3Hz, 1H), 7.20-7.26 (m, 1H), 7.36-7.40 (m, 1H)

Referential Example 23 Synthesis of 3-benzyloxy-2-methylaniline(referential compound 23)

Zinc (52.3 g, 800 mmol) was added, in a divided manner, at 0° C. to asolution of 49.3 g (203 mmol) of 2-benzyloxy-6-nitrotoluene (referentialcompound 22-1) in 400 ml of methanol and 200 ml of acetic acid in anargon stream with stirring and the mixture was stirred for 1 hour.

After the reaction was finished, the reaction solution was poured into1,600 ml of water and the mixture was extracted with 1,500 ml of ethylacetate. The organic layer was successively washed with water, asaturated aqueous solution of sodium hydrogen carbonate and a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated in vacuo to give 44.0 g of the title compoundas a brown oily substance (yield: quantitative).

Rf value: 0.22 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (EI,m/z): 213 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 2.11 (s, 3H), 3.64 (brs,2H), 5.05 (s, 2H), 6.36-6.39 (m, 1H), 6.41 (d, J=8.3 Hz, 1H), 6.93-6.99(m, 1H), 7.29-7.46 (m, 5H)

Referential Example 24 Synthesis of 3-benzyloxy-2-methylacetanilide(referential compound 24-1)

Acetic anhydride (28.3 ml, 299 mmol) was added to a solution of 44.0 g(206 mmol) of 3-benzyloxy-2-methylaniline (referential compound 23) in400 ml of ethyl acetate and the mixture was heated to reflux withstirring for 30 minutes.

After the reaction was finished, the reaction solution was poured into2,000 ml of hexane and the resulting solid was filtered off and washedwith hexane to give 44.9 g of the title compound as white powder (yield:85%).

Rf value: 0.24 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 256 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 2.04 (s, 3H), 2.06(s, 3H), 5.11 (s, 2H), 6.87. (d, J=7.9 Hz, 1H), 6.96-7.00 (m, 1H), 7.09(dd, J1=7.9 Hz, J2=7.9 Hz, 1H), 7.29-7.48 (m, 5H), 9.31 (brs, 1H)

As hereunder, the referential compounds 24-2 to 24-4 were produced inaccordance with the production process for the referential compound24-1.

3-Methoxy-2-methylacetanilide (referential compound 24-2)

Rf value: 0.20 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 180 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 2.00 (s, 3H), 2.03(s, 3H), 3.78 (s, 3H), 6.78 (d, J=8.0 Hz, 1H), 6.93-6.97 (m, 1H),7.07-7.13 (m, 1H), 9.29 (brs, 1H)

3-Ethoxy-2-methylacetanilide (referential compound 24-3)

Rf value: 0.10 (n-hexane:ethyl acetate=5:1 (v/v)) Mass spectrum (CI,m/z): 194 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.42 (t, J=6.9 Hz, 3H),2.13 (s, 3H), 2.20 (s, 3H), 4.02 (q, J=6.9 Hz, 2H), 6.69 (d, J=8.1 Hz,1H), 6.94 (brs, 1H), 7.13 (dd, J1=8.1 Hz, J2=8.1 Hz, 1H), 7.35 (d, J=8.1Hz, 1H)

2-Methyl-3-n-propoxyacetanilide (referential compound 24-4)

Rf value: 0.33 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 208 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.00 (t, 7.4 Hz, 3H),1.68-1.80 (m, 2H), 2.01 (s, 3H), 2.03 (s, 3H), 3.91 (t, J=6.3 Hz, 2H),6.76 (d, J=8.1 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.04-7.10 (m, 1H), 9.28(brs, 1H)

Referential Example 25 Synthesis of 1-acetyl-4-benzyloxy-1H-indazole(referential compound 25-1)

Tetra-n-butylammonium bromide (1.61 g, 4.99 mmol), 19.6 g (200 mmol) ofpotassium acetate and 450 ml of ethyl acetate were added to 25.5 g (100mmol) of 3-benzyloxy-2-methylacetanilide (referential compound 24-1).After that, 28.4 ml (300 mmol) of acetic anhydride and 26.8 ml (200mmol) of isoamyl nitrite were added thereto with stirring under an argonstream and the mixture was heated to reflux with stirring for 9 hours.

After the reaction was finished, the reaction solution was added to 500ml of water to separate into layers. The organic layer was successivelywashed with a saturated aqueous solution of sodium hydrogen carbonateand a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultingresidue was subjected to a silica gel column chromatography (elutingsolvent: n-hexane:ethyl acetate=50:1 to 20:1 (v/v)) and the fractioncontaining the aimed substance was concentrated in vacuo to give 17.7 gof the title compound as yellow powder (yield: 66%).

Rf value: 0.41 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 267 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 2.78 (s, 3H), 5.24 (s,2H), 6.78 (d, J=7.9 Hz, 1H), 7.34-7.50 (m, 6H), 8.00-8.03 (m, 1H), 8.24(d, J=1.0 Hz, 1H)

As hereunder, the referential compounds 25-2 to 25-4 were produced inaccordance with the production process for the referential compound25-1.

1-Acetyl-4-methoxy-1H-indazole (referential compound 25-2)

Rf value: 0.53 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 191 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 2.78 (s, 3H), 3.98 (s,3H), 6.71 (d, J=8.1 Hz, 1H), 7.46 (dd, J1=8.3 Hz, J2=8.1 Hz, 1H),7.98-8.01 (m, 1H), 8.20 (d, J=0.7 Hz, 1H)

1-Acetyl-4-ethoxy-1H-indazole (referential compound 25-3)

Rf value: 0.55 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 205 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.50 (t, J=7.2 Hz, 3H),2.78 (s, 3H), 4.21 (q, J=7.2 Hz, 2H), 6.69 (d, J=7.8 Hz, 1H), 7.40-7.48(m, 1H), 7.99 (dd, J1=8.3 Hz, J2=0.7 Hz, 1H), 8.20 (d, J=0.7 Hz, 1H)

1-Acetyl-4-n-propoxy-1H-indazole (referential compound 25-4)

Rf value: 0.54 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 219 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.10 (t, J=7.3 Hz, 3H),1.84-1.97 (m, 2H), 2.78 (s, 3H), 4.10 (t, 6.6 Hz, 2H), 6.69 (d, J=8.0Hz, 1H), 7.44 (dd, J1=8.3 Hz, J2=8.0 Hz, 1H), 7.95-7.99 (m, 1H), 8.20(d, J=0.7 Hz, 1H)

Referential Example 26 Synthesis of 4-benzyloxy-5-bromo-1H-indazole(referential compound 26-1)

N-Bromosuccinimide (13.0 g, 73.0 mmol) was added, at 0° C., to asolution of 17.7 g (66.5 mmol) of 1-acetyl-4-benzyloxy-1H-indazole(referential compound 25-1) in 330 ml of tetrahydrofuran in an argonstream with stirring and the mixture was stirred for 30 minutes and thenstirred at room temperature for 15 hours.

After that, 300 ml of methanol and 130 ml of a 1N aqueous solution ofsodium hydroxide were added to the reaction solution and the mixture wasstirred at room temperature for 30 minutes.

After the reaction was finished, the reaction solution was neutralizedwith 1N aqueous hydrochloric acid solution and concentrated in vacuo.The resulting residue was extracted with 500 ml of ethyl acetate and theorganic layer was successively washed with a saturated aqueous solutionof sodium hydrogen carbonate and a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and concentrated invacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=6:1 to 4:1(v/v)) and the fraction containing the aimed substance was concentratedin vacuo to give 13.6 g of the title compound as light orange powder(yield: 67%).

Rf value: 0.25 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 302, 304 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 5.40 (s, 2H), 7.10(dd, J1=8.8 Hz, J2=1.0 Hz, 1H), 7.33-7.44 (m, 3H), 7.49-7.55 (m, 3H),8.06 (d, J=1.0 Hz, 1H), 10.14 (brs, 1H)

As hereunder, the referential compounds 26-2 to 26-5 were produced inaccordance with the production process for the referential compound26-1.

5-Bromo-4-methoxy-1H-indazole (referential compound 26-2)

Rf value: 0.17 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 226, 228 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 4.25 (s, 3H), 7.06(dd, J1=8.7 Hz, J2=1.0 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 8.23 (d, J=1.0Hz, 1H), 10.09 (brs, 1H)

5-Bromo-4-ethoxy-1H-indazole (referential compound 26-3)

Rf value: 0.30 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 241, 243 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.52 (t, J=6.9 Hz,3H), 4.46 (q, J=6.9 Hz, 2H), 7.06 (dd, J1=8.8 Hz, J2=1.0 Hz, 1H), 7.49(d, J=8.8 Hz, 1H), 8.14 (d, J=1.0 Hz, 1H), 10.11 (brs, 1H)

5-Bromo-4-n-propoxy-1H-indazole (referential compound 26-4)

Rf value: 0.28 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 255, 257 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.14 (t, J=7.4 Hz,3H), 1.86-1.99 (m, 2H), 4.37 (t, J=6.5 Hz, 2H), 7.05 (dd, J1=8.8 Hz,J2=1.1 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 8.16 (d, J=1.1 Hz, 1H), 10.17(brs, 1H)

5-Bromo-4-hydroxy-1-(tetrahydropyran-2-yl)-1H-indazole (referentialcompound 26-5)

Rf value: 0.51 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 296, 298 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.60-1.84 (m, 3H),2.05-2.19 (m, 2H), 2.47-2.60 (m, 1H), 3.69-3.77 (m, 1H), 3.98-4.16 (m,1H), 5.63-5.70 (m, 1H), 5.95 (s, 1H), 7.07 (dd, J1=8.9 Hz, J2=0.8 Hz,1H), 7.38 (d, J=8.9 Hz, 1H), 8.09 (d, J=0.8 Hz, 1H)

Referential Example 27 Synthesis of4-benzyloxy-5-bromo-2-(tetrahydropyran-2-yl)-2H-indazole (referentialcompound 27-1)

Pyridinium p-toluenesulfonate (3.39 g, 13.5 mmol) and 450 ml ofmethylene chloride were added to 13.6 g (44.9 mmol) of4-benzyloxy-5-bromo-1H-indazole (referential compound 26-1). After that,12.3 ml (135 mmol) of 3,4-dihydro-2H-pyran was added thereto at 0° C.with stirring in an argon stream and the mixture was stirred for 30minutes. After that, it was stirred at room temperature for 3 hours.

After the reaction was finished, the reaction solution was poured into300 ml of a saturated aqueous solution of sodium hydrogen carbonate toseparate into layers. The organic layer was successively washed with a10% aqueous solution of citric acid, water and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue was subjected to a silicagel column chromatography (eluting solvent: n-hexane:ethyl acetate=6:1(v/v)) and a high polar fraction (Rf value: 0.36 (n-hexane:ethylacetate=2:1 (v/v)) was concentrated in vacuo to give 15.5 g of the titlecompound as an orange oily substance (yield: 89%).

Rf value: 0.36 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 386, 388 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.66-1.80 (m, 3H),2.02-2.23 (m, 3H), 3.73-3.81 (m, 1H), 4.09-4.14 (m, 1H), 5.27 (s, 2H),5.60-5.64 (m, 1H), 7.32-7.43 (m, 5H), 7.51-7.54 (m, 2H), 8.07 (s, 1H)

As hereunder, the referential compounds 27-2 to 27-8 were produced inaccordance with the production process for the referential compound27-1.

5-Iodo-4-nitro-2-(tetrahydropyran-2-yl)-2H-indazole (referentialcompound 27-2)

Rf value: 0.37 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 374 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.67-1.83 (m, 3H),2.04-2.30 (m, 3H), 3.76-3.84 (m, 1H), 4.12-4.18 (m, 1H), 5.69-5.73 (m,1H), 7.66 (dd, J1=9.0 Hz, J2=1.0 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 8.56(d, J=1.0 Hz, 1H)

5-Iodo-2-(tetrahydropyran-2-yl)-2H-indazole (referential compound 27-3)

Rf value: 0.39 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 328 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.64-1.80 (m, 3H),2.02-2.25 (m, 3H), 3.73-3.82 (m, 1H), 4.09-4.16 (m, 1H), 5.63-5.68 (m,1H), 7.45-7.53 (m, 2H), 8.06-8.08 (m, 1H), 8.09 (s, 1H)

5-Nitro-2-(tetrahydropyran-2-yl)-2H-indazole (referential compound 27-4)

Rf value: 0.34 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 248 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.64-1.91 (m, 3H),2.00-2.22 (m, 2H), 2.27-2.39 (m, 1H), 3.77-3.86 (m, 1H), 4.12-4.20 (m,1H), 5.70-5.74 (m, 1H), 7.77 (ddd, J1=9.5 Hz, J2=0.7 Hz, J3=0.5 Hz, 1H),8.10 (dd, J1=9.5 Hz, J2=2.2 Hz, 1H), 8.47 (d, J=0.5 Hz, 1H), 8.75 (dd,J1=2.2 J2=0.7 Hz, 1H)

5-Iodo-2-(tetrahydropyran-2-yl)-4-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-indazole(referential compound 27-5)

Mass spectrum (EI, m/z): 456 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm):1.26-1.82 (m, 9H), 1.88-2.07 (m, 2H), 2.25-2.53 (m, 1H), 3.25-3.40 (m,2H), 3.48-3.91 (m, 6H), 4.55-4.61 (m, 1H), 5.58-5.84 (m, 1H), 7.41 (d,J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 8.21(s, 1H)

5-tert-Butyldimethylsilyloxy-4-formyl-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 27-6)

Rf value: 0.63 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 361 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.30 (s, 6H), 1.05 (s,9H), 1.50-2.30 (m, 6H), 3.70-3.85 (m, 1H), 4.05-4.20 (m, 1H), 5.70-5.80(m, 1H), 6.99 (d, J=9.3 Hz, 1H), 7.93 (d, J=9.3 Hz, 1H), 8.82 (s, 1H),10.54 (s, 1H)

5-(tert-Butyldimethylsilyloxy)-4-methylcarbonyl-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 27-7)

Property: white powder Rf value: 0.37 (n-hexane:ethyl acetate=2:1 (v/v))Mass spectrum (CI, m/z): 375 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.32(s, 6H), 1.02 (s, 9H), 1.62-1.82 (m, 3H), 2.00-2.13 (m, 1H), 2.15-2.30(m, 2H), 2.69 (s, 3H), 3.73-3.82 (m, 1H), 4.06-4.15 (m, 1H), 5.65-5.73(m, 1H), 6.99 (d, J=9.4 Hz, 1H), 7.82 (d, J=9.4 Hz, 1H), 8.67 (s, 1H)

5-Bromo-4-methoxy-2-(tetrahydropyran-2-yl)-2H-indazole (referentialcompound 27-8)

Rf value: 0.27 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 310, 312 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.68-1.81 (m, 3H),2.04-2.29 (m, 3H), 3.75-3.83 (m, 1H), 4.08-4.36 (m, 4H), 5.63-5.68 (m,1H), 7.31 (dd, J1=9.0 Hz, J2=1.0 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 8.28(d, J=1.0 Hz, 1H)

Referential Example 28 Synthesis of4-benzyloxy-5-bromo-1-(tetrahydropyran-2-yl)-1H-indazole (referentialcompound 28-1)

In the synthesis for referential compound 27-1, a low polar fraction (Rfvalue: 0.52 (n-hexane:ethyl acetate=2:1 (v/v)) was concentrated in vacuoto give 1.18 g of the title compound as a yellow oily substance (yield:7%).

Rf value: 0.52 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 386, 388 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.66-1.79 (m, 3H),2.04-2.15 (m, 2H), 2.49-2.55 (m, 1H), 3.69-3.78 (m, 1H), 3.98-4.04 (m,1H), 5.36 (s, 2H), 5.64-5.68 (m, 1H), 7.20 (dd, J1=8.9 Hz, J2=0.9 Hz,1H), 7.31-7.43 (m, 3H), 7.49-7.60 (m, 3H), 7.99 (d, J=0.9 Hz, 1H)

As hereunder, the referential compounds 28-2 to 28-4 were produced inaccordance with the production process for the referential compound28-1.

5-Bromo-4-ethoxy-1-(tetrahydropyran-2-yl)-1H-indazole (referentialcompound 28-2)

Rf value: 0.60 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 324, 326 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.50 (t, J=6.9 Hz,3H), 1.65-1.84 (m, 3H), 2.03-2.16 (m, 2H), 2.47-2.55 (m, 1H), 3.69-3.77(m, 1H), 3.99-4.04 (m, 1H), 4.42 (q, J=6.9 Hz, 2H), 5.60-5.68 (m, 1H),7.15 (dd, J=8.8 Hz, J=1.0 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 8.07 (d,J=1.0 Hz, 1H)

5-Bromo-4-n-propoxy-1-(tetrahydropyran-2-yl)-1H-indazole (referentialcompound 28-3)

Rf value: 0.50 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 338, 340 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.12 (t, J=7.3 Hz,3H), 1.56-1.81 (m, 3H), 1.84-1.96 (m, 2H), 2.02-2.18 (m, 2H), 2.47-2.60(m, 1H), 3.68-3.77 (m, 1H), 3.99-4.04 (m, 1H), 4.33 (t, J=6.6 Hz, 2H),5.63-5.68 (m, 1H), 7.15 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 7.48 (d, J=8.8Hz, 1H), 8.08 (d, J=0.7 Hz, 1H)

4-Benzyloxy-1-(tetrahydropyran-2-yl)-1H-indazole (referential compound28-4)

Rf value: 0.70 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 308 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.56-1.83 (m, 3H),2.05-2.18 (m, 2H), 2.45-2.64 (m, 1H), 3.69-3.78 (m, 1H), 4.01-4.09 (m,1H), 5.23 (s, 2H), 5.65-5.73 (m, 1H), 6.55 (d, J=7.6 Hz, 1H), 7.16 (dd,J1=7.6 Hz, J2=0.7 Hz, 1H), 7.23-7.50 (m, 6H), 8.13 (d, J=0.7 Hz, 1H)

Referential Example 29 Synthesis of1-acetyl-5-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolanyl)-1H-indazole(referential compound 29-1)

Dichlorobis(triphenylphosphine)palladium (270 mg, 0.38 mmol) and 18 mlof 1,4-dioxane were added to 1.1 g (3.8 mmol) of1-acetyl-5-iodo-1H-indazole (referential compound 12-1). After that, 1.7ml (12 mmol) of 4,4,5,5-tetramethyl[1,3,2]dioxaborolane and 1.6 ml (12mmol) of triethylamine were added thereto with stirring in an argonstream and the mixture was stirred at 80° C. for 1 hour.

After the reaction was finished, the reaction solution was poured into50 ml of water and the mixture was extracted with 200 ml of ethylacetate. The organic layer was successively washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=10:1 (v/v)) and the fraction containing the aimedsubstance was concentrated in vacuo to give 0.70 g of the title compoundas yellow powder (yield: 64%).

Rf value: 0.41 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 287 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (s, 12H), 2.79 (s,3H), 7.98 (dd, J1=8.3 Hz, J2=1.0 Hz, 1H), 8.12 (d, J=0.7 Hz, 1H),8.22-8.24 (m, 1H), 8.42 (ddd, J1=8.3 Hz, J2=1.0 Hz, J3=0.7 Hz, 1H)

As hereunder, the referential compounds 29-2 to 29-6 were produced inaccordance with the production process for the referential compound29-1.

2-(Tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-2H-indazole(referential compound 29-2)

Rf value: 0.29 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 328 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.36 (s, 12H), 1.63-1.84(m, 3H), 2.03-2.27 (m, 3H), 3.74-3.83 (m, 1H), 4.08-4.16 (m, 1H),5.65-5.70 (m, 1H), 7.62-7.71 (m, 2H), 8.18 (s, 1H), 8.24-8.25 (m, 1H)

4-Benzyloxy-1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)-1H-indazole(referential compound 29-3)

Rf value: 0.31 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 435 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.36 (s, 12H),1.65-1.79 (m, 3H), 2.02-2.18 (m, 2H), 2.49-2.63 (m, 1H), 3.70-3.79 (m,1H), 4.01-4.07 (m, 1H), 5.37 (s, 2H), 5.66-5.71 (m, 1H), 7.24 (dd,J1=8.4 Hz, J2=0.7 Hz, 1H), 7.29-7.41 (m, 3H), 7.57-7.62 (m, 2H), 7.72(d, J=8.4 Hz, 1H), 8.09 (d, J=0.7 Hz, 1H)

4-Ethoxy-1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)-1H-indazole(referential compound 29-4)

Rf value: 0.32 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 373 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.36 (s, 12H), 1.45 (t,J=7.1 Hz, 3H), 1.57-1.79 (m, 3H), 2.02-2.17 (m, 2H), 2.50-2.62 (m, 1H),3.69-3.78 (m, 1H), 4.00-4.06 (m, 1H), 4.35 (q, J=7.1 Hz, 2H), 5.62-5.70(m, 1H), 7.21 (dd, J1=8.4 Hz, J2=0.9 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H),8.10 (d, J=0.9 Hz, 1H)

4-n-Propoxy-1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)-1H-indazole(referential compound 29-5)

Rf value: 0.31 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 387 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.10 (t, J=7.4 Hz, 3H),1.36 (s, 12H), 1.64-1.79 (m, 3H), 1.81-1.93 (m, 2H), 2.01-2.16 (m, 2H),2.49-2.62 (m, 1H), 3.69-3.78 (m, 1H), 4.00-4.05 (m, 1H), 4.29 (t, J=6.4Hz, 2H), 5.64-5.69 (m, 1H), 7.18 (dd, J1=8.5 Hz, J2=0.9 Hz, 1H), 7.67(d, J=8.5 Hz, 1H), 8.11 (d, J=0.9 Hz, 1H)

4-Cyclopropyloxy-1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)-1H-indazole(referential compound 29-6)

Rf value: 0.44 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 385 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.68-0.73 (m, 2H),0.90-0.95 (m, 2H), 1.35 (s, 12H), 1.65-1.83 (m, 3H), 2.03-2.18 (m, 2H),2.51-2.64 (m, 1H), 3.70-3.78 (m, 1H), 4.01-4.05 (m, 1H), 4.35-4.41 (m,1H), 5.65-5.73 (m, 1H), 7.17 (dd, J1=8.4 Hz, J2=0,7 Hz, 1H), 7.64 (d,J=8.4 Hz, 1H), 8.28 (d, J=0.7 Hz, 1H)

Referential Example 30 Synthesis of4-nitro-2-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)-2H-indazole(referential compound 30-1)

A 1:1 adduct of 1,1′-bis(diphenylphosphino)ferrocene palladium (II)chloride with dichloromethane (1.43 g, 1.75 mmol), 2.13 g (21.7 mmol) ofpotassium acetate, 2.75 g (10.8 mmol) of bis(pinacolato)diboron and 100ml of N,N-dimethylformamide were added to 2.68 g (7.18 mmol) of5-iodo-4-nitro-2-(tetrahydropyran-2-yl)-2H-indazole (referentialcompound 27-2) and the mixture was stirred at 80° C. for 2.5 hours in anargon stream.

After the reaction was finished, the reaction solution was poured into400 ml of water and the mixture was extracted with 500 ml of toluene.The organic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and concentrated invacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=4:1 (v/v)) andthe fraction containing the aimed substance was concentrated in vacuo togive 717 mg of the title compound as yellow powder (yield: 27%).

Rf value: 0.29 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 374 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.46 (s, 12H),1.67-1.83 (m, 3H), 2.04-2.10 (m, 1H), 2.21-2.30 (m, 2H), 3.77-3.85 (m,1H), 4.15-4.20 (m, 1H), 5.72-5.76 (m, 1H), 7.37 (d, J=8.5 Hz, 1H), 8.07(dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 8.77 (d, J=0.7 Hz, 1H)

As hereunder, the referential compounds 30-2 to 30-4 were produced inaccordance with the production process for the referential compound30-1.

2-(Tetrahydropyran-2-yl)-4-[2-(tetrahydropyran-2-yloxy)ethyl]-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)-2H-indazole(referential compound 30-2)

Rf value: 0.29 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 456 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.36 (s, 12H), 1.39-1.80(m, 9H), 2.00-2.22 (m, 2H), 2.50-2.59 (m, 1H), 3.35-3.47 (m, 1H),3.52-3.78 (m, 5H), 3.92-4.08 (m, 2H), 4.55-4.59 (m, 1H), 5.66-5.71 (m,1H), 7.39 (d, J=8.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 8.18 (s, 1H)

4-Benzyloxy-2-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)-2H-indazole(referential compound 30-3)

Rf value: 0.37 (toluene:ethyl acetate=19:1 (v/v)) Mass spectrum (EI,m/z): 434 (M⁺) ¹H-NMR spectrum (DMSO₄-d₆, δ ppm): 1.31 (s, 12H),1.53-1.80 (m, 3H), 1.90-2.10 (m, 2H), 2.19-2.33 (m, 1H), 3.65-3.80 (m,1H), 3.95-4.07 (m, 1H), 5.38 (s, 2H), 5.71-5.76 (m, 1H), 7.25 (dd,J1=8.8 Hz, J2=1.0 Hz, 1H), 7.30-7.44 (m, 4H), 7.66-7.71 (m, 2H),8.79-8.80 (m, 1H)

4-Methoxy-2-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)-2H-indazole(referential compound 30-4)

Rf value: 0.20 (n-hexane:ethyl acetate=2:1 (v/v)′) Mass spectrum (EI,m/z): 358 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.36 (s, 12H), 1.66-1.77(m, 3H), 2.03-2.28 (m, 3H), 3.74-3.85 (m, 1H), 4.08-4.16 (m, 4H),5.63-5.67 (m, 1H), 7.36 (dd, J1=8.8 Hz, J2=1.0 Hz, 1H), 7.54 (d, J=8.8Hz, 1H), 8.28 (d, J=1.0 Hz, 1H)

Referential Example 31 Synthesis of4-methoxycarbonylmethyl-5-nitro-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 31)

A solution of 24.6 g (100 mmol) of5-nitro-2-(tetrahydropyran-2-yl)-2H-indazole (referential compound 27-4)and 10.5 ml (120 mmol) of methyl chloroacetate in 400 ml ofN,N-dimethylformamide was dropped into a solution of 33.7 g (300 mmol)of potassium tert-butoxide in 100 ml of N,N-dimethylformamide at −40° C.during 50 minutes and the mixture was stirred at −40° C. for 30 minutes.

After the reaction was finished, temperature of the reaction solutionwas returned to room temperature, the solution was neutralized with 1Nhydrochloric acid and 4,000 ml of water was added thereto. The resultingsolid was filtered off and successively washed with 500 ml of water, 400ml of methanol and 300 ml of diethyl ether to give 50.4 g of the titlecompound as pale yellow powder (yield: 79%).

Rf value: 0.21 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 320 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.68-1.81 (m, 3H),2.03-2.16 (m, 2H), 2.28-2.35 (m, 1H), 3.72 (s, 3H), 3.75-3.85 (m, 1H),4.14-4.20 (m, 1H), 4.29 (s, 2H), 5.67-5.72 (m, 1H), 7.71 (dd, J1=9.3 Hz,J2=0.5 Hz, 1H), 8.02 (d, J=9.3 Hz, 1H), 8.47 (d, J=0.5 Hz, 1H)

Referential Example 32 Synthesis of5-amino-4-methoxycarbonylmethyl-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 32)

Tetrahydrofuran (50 ml) and 20 ml of methanol were added to 2.88 g (9.02mmol) of4-methoxycarbonylmethyl-5-nitro-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 31), then a suspension of 4.40 g of 5%palladium-carbon (wet) in 20 ml of ethyl acetate was added thereto andthe mixture was stirred in a hydrogen atmosphere at room temperature for1.5 hours.

After the reaction was finished, the reaction solution was filteredthrough Celite and the filtrate was concentrated in vacuo to give 2.52 gof the title compound as a brown oily substance (yield: 97%).

Rf value: 0.19 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 289 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.54-1.78 (m, 3H),1.92-2.01 (m, 2H), 2.08-2.22 (m, 1H), 3.58 (s, 3H), 3.61-3.73 (m, 3H),3.90-4.00 (m, 1H), 4.79 (brs, 2H), 5.56-5.61 (m, 1H), 6.84 (d, J=9.0 Hz,1H), 7.30 (dd, J1=9.0 Hz, J2=1.0 Hz, 1H), 8.05 (d, J=1.0 Hz, 1H)

Referential Example 33 Synthesis of5-tert-butoxycarbonylamino-4-methoxycarbonylmethyl-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 33)

Di-tert-butyl dicarbonate (15 g, 69 mmol) was added to a solution of 17g (60 mmol) of5-amino-4-methoxycarbonylmethyl-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 32) in 75 ml of tetrahydrofuran with stirring inan argon stream and the mixture was heated to reflux with stirring for1.5 hours.

After the reaction was finished, the reaction solution was concentratedin vacuo, 75 ml of a saturated aqueous solution of ammonium chloride wasadded to the resulting residue and the mixture was extracted with 250 mlof ethyl acetate. The organic layer was successively washed with waterand a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated in vacuo. n-Hexane wasadded to the resulting residue and the resulting solid was filtered offto give 16 g of the title compound as slightly brown powder (yield:69%).

Rf value: 0.41 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 389 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.44 (s, 9H), 1.53-1.83(m, 3H), 1.92-2.29 (m, 3H), 3.57 (s, 3H), 3.67-3.76 (m, 1H), 3.88 (s,2H), 3.94-4.04 (m, 1H), 5.68-5.73 (m, 1H), 7.14 (dd, J1=9.0 Hz, J2=1.0Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 8.48 (d, J=1.0 Hz, 1H), 8.63 (brs, 1H)

Referential Example 34 Synthesis of5-tert-butoxycarbonylamino-4-(2-hydroxyethyl)-2-(tetrahydropyran-2-yl)-2H-indazole(referential Compound 34)

Sodium borohydride (3.4 g, 90 mmol) was dividedly added to a solution of12 g (30 mmol) of5-tert-butoxycarbonylamino-4-methoxycarbonylmethyl-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 33) in 100 ml of methanol with stirring on a waterbath and the mixture was stirred on the water bath for 2 hours. Further,1.1 g (30 mmol) of sodium borohydride was dividedly added thereto andthe mixture was stirred on the water bath for 2 hours.

After the reaction was finished, the reaction solution was graduallypoured into 300 ml of a saturated aqueous solution of ammonium chlorideand the mixture was extracted with 500 ml of ethyl acetate. The organiclayer was successively washed with water and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue was recrystallized fromdiethyl ether/n-hexane to give 10 g of the title compound as whitepowder, (yield: 95%).

Rf value: 0.17 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 361 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.45 (s, 9H), 1.54-1.82(m, 3H), 1.91-2.30 (m, 3H), 2.95 (t, J=6.7 Hz, 2H), 3.57-3.76 (m, 2H),3.97-4.02 (m, 1H), 4.91-4.94 (m, 1H), 5.67-5.72 (m, 1H), 7.21 (d, J=9.3Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 8.49 (s, 1H), 8.55 (brs, 1H)

Referential Example 35 Synthesis of5-amino-4-(2-hydroxyethyl)-1H-indazole dihydrochloride (referentialcompound 35)

A solution of about 4.2N hydrogen chloride/ethanol (200 ml) was added atroom temperature to a solution of 16 g (43 mmol) of5-tert-butoxycarbonylamino-4-(2-hydroxyethyl)-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 34) in 100 ml of ethanol and the mixture wasstirred at room temperature for 2 hours.

After the reaction was finished, 200 ml of diethyl ether was added tothe reaction solution and the resulting solid was filtered off to give9.6 g of the title compound as white powder (yield: 89%).

Mass spectrum (CI, m/z): 178 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm):3.22 (t, J=6.6 Hz, 2H), 3.75 (t, J=6.6 Hz, 2H), 7.43 (d, J=8.8 Hz, 1H),7.51 (dd, J1=8.8 Hz, J2=1.0 Hz, 1H), 8.24 (d, J=1.0 Hz, 1H), 10.25 (brs,3H)

Referential Example 36 Synthesis of5-hydroxy-4-methylcarbonyl-1H-indazole (referential compound 36)

Aluminum chloride (30 g, 220 mmol) was added to a solution of 10 g (67mmol) of 5-methoxy-1H-indazole (cf. R. A. Bartsche, et al., J.Heterocyclic Chem., 21, 1063 (1984)) in 200 ml of 1,2-dichloroethane atroom temperature in an argon stream and the mixture was stirred for 30minutes. After that, 12 ml (170 mmol) of acetyl chloride was addedthereto at room temperature and the mixture was stirred at 60° C. for2.5 hours.

After the reaction was finished, the reaction solution was allowed tocool, water was added thereto and the mixture was extracted withchloroform. The organic layer was successively washed with a saturatedaqueous solution of sodium hydrogen carbonate and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue was washed with chloroformto give 3.6 g of the title compound as yellow powder (yield: 30%).

Melting point: 188 to 191° C. Rf value: 0.14 (n-hexane:ethyl acetate=2:1(v/v)) Mass spectrum (CI, m/z): 177 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δppm): 2.79 (s, 3H), 7.05 (d, J=8.9 Hz, 1H), 7.81 (dd, J1=8.9 Hz, J2=0.9Hz, 1H), 8.25 (d, J=0.9 Hz, 1H), 12.61 (brs, 1H), 13.38 (brs, 1H)

Referential Example 37 Synthesis of 4-formyl-5-methoxy-1H-indazole(referential compound 37)

Aluminum chloride (45.0 g, 337 mmol) was added to a solution of 25.0 g(169 mmol) of 5-methoxy-1H-indazole in 500 ml of methylane chloride inan argon stream and the mixture was stirred at room temperature for 30minutes. This was cooled down to −10° C., 17.5 ml (193 mmol) ofdichloromethyl methyl ether was dropped thereinto during 20 minutes andthe mixture was stirred at 0° C. for 2 hours.

After the reaction was finished, 300 ml of a mixed solution ofmethanol:water=1:1 (v/v) was gradually added to the reaction solution at0° C. and the resulting solid was filtered off, washed with chloroform.Then 300 ml of chloroform, 150 ml of methanol and 150 ml of a saturatedaqueous solution of sodium bicarbonate were added to the resulting solidand the mixture was stirred at room temperature for 1 hour. Theresulting mixed solution was extracted with 150 ml of a mixed solvent ofchloroform:methanol=2:1 (v/v) and the organic layer was dried overanhydrous magnesium sulfate and concentrated in vacuo. Chloroform wasadded to the resulting solid, the mixture was subjected to an ultrasonictreatment. The solid was filtered off and washed with chloroform to give7.20 g of the title compound as green powder (yield: 24%).

Rf value: 0.50 (ethyl acetate) Mass spectrum (CI, m/z): 177 (M⁺+1)¹H-NMR spectrum (DMSO-d₆, δ ppm): 4.00 (s, 3H) 7.40 (d, J=9.0 Hz, 1H),7.93 (dd, J1=9.0 Hz, J2=1.0 Hz, 1H), 8.43 (d, J=1.0 Hz, 1H), 10.57 (s,1H), 13.32 (brs, 1H)

Referential Example 38 Synthesis of 4-formyl-5-hydroxy-1H-indazolemonohydrobromide (referential compound 38)

A solution of 25.0 g (100 mmol) of boron tribromide in 50 ml ofmethylene chloride was added to a solution of 10.1 g (57.3 mmol) of4-formyl-5-methoxy-1H-indazole (referential compound 37) in 50 ml ofmethylene chloride and the mixture was stirred at room temperature for 2hours. After that, 50.0 ml of a 1.0M boron tribromide/methylene chloridesolution was added thereto and the mixture was stirred for 7 hours.

After the reaction was finished, the reaction solution was cooled downto 0° C. and methanol was gradually added thereto. The mixture wasconcentrated in vacuo, a mixed solvent of diethyl ether:methanol=9:1(v/v) was added thereto and the resulting solid was filtered off to give11.2 g of the title compound as light gray powder (yield: 81%).

Rf value: 0.35 (chloroform:methanol:28% aqueous ammonia=10:1:0.1(v/v/v)) Mass spectrum (CI, m/z): 163 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δppm): 7.09 (d, J=9.0 Hz, 1H), 7.78 (dd, J1=9.0 Hz, J2=1.0 Hz, 1H), 8.36(d, J=1.0 Hz, 1H), 10.53 (s, 1H), 10.66 (brs, 2H)

Referential Example 39 Synthesis of5-tert-butyldimethylsilyloxy-4-formyl-1H-indazole (referential compound39-1)

N,N-Diisopropylethylamine (1.50 ml, 8.61 mmol) and 700 mg (4.64 mmol) oftert-butyldimethylsilyl chloride were added at 0° C. to a solution of955 mg (3.93 mmol) of 4-formyl-5-hydroxy-1H-indazole monohydrobromide(referential compound 38) in 15 ml of tetrahydrofuran and the mixturewas stirred at room temperature for 15 hours.

After the reaction was finished, water was added to the reactionsolution and the mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresulting residue was subjected to a silical gel column chromatography(eluting solvent: n-hexane:ethyl acetate=2:1 to 1:1 (v/v)) and thefraction containing the aimed substance was concentrated in vacuo togive 964 mg of the title compound as white solid (yield: 88%).

Rf value: 0.45 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 277 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.31 (s, 6H), 1.06 (s,9H), 7.11 (d, J=9.1 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H), 8.59 (s, 1H), 10.63(s, 1H)

As hereunder, the referential compound 39-2 was produced in accordancewith the production process for the referential compound 39-1.

5-(tert-Butyldimethylsilyloxy)-4-methylcarbonyl-1H-indazole (referentialcompound 39-2)

Rf value: 0.28 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 291 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.35 (s, 6H), 1.04 (s,9H), 2.73 (s, 3H), 7.28 (d, J=9.4 Hz, 1H), 7.89 (dd, J1=9.4 Hz, J2=0.8Hz, 1H), 8.83 (d, J=0.8 Hz, 1H)

Referential Example 40 Synthesis of4-formyl-5-hydroxy-2-(tetrahydropyran-2-yl)-2H-indazole (referentialcompound 40-1)

A 1.0 M solution (34.0 ml, 34.0 mmol) of tetrabutylammoniumfluoride/tetrahydrofuran was added, at 0° C., to a solution of 10.1 g(28.0 mmol) of5-tert-butyldimethylsilyloxy-4-formyl-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 27-6) in 150 ml of tetrahydrofuran and the mixturewas stirred at 0° C. for 1.5 hours.

After the reaction was finished, water was added to the reactionsolution and the mixture was extracted with chloroform. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresulting residue was subjected to a silica gel column chromatography(eluting solvent: n-hexane:ethyl acetate=6:1 to 3:2 (v/v)) and thefraction containing the aimed substance was concentrated in vacuo togive 4.5 g of the title compound as a yellow foamy substance (yield:65%)

Rf value: 0.10 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 247 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.60-1.90 (m, 3H),1.97-2.30 (m, 3H), 3.70-3.85 (m, 1H), 4.05-4.20 (m, 1H), 5.60-5.75 (m,1H), 7.00 (d, J=9.3 Hz, 1H), 7.92 (dd, J1=9.3 Hz, J2=1.0 Hz, 1H), 8.31(d, J=1.0 Hz, 1H), 10.25 (s, 1H), 12.10 (brs, 1H)

As hereunder, the referential compound 40-2 was produced in accordancewith the production process for the referential compound 40-1.

5-Hydroxy-4-methylcarbonyl-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 40-2)

Property: yellow powder Rf value: 0.28 (n-hexane:ethyl acetate=2:1(v/v)) Mass spectrum (CI, m/z): 261 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δppm): 1.62-1.84 (m, 3H), 2.01-2.12 (m, 1H), 2.13-2.25 (m, 2H), 2.74 (s,3H), 3.71-3.82 (m, 1H), 4.08-4.16 (m, 1H), 5.62-5.67 (m, 1H), 7.01 (d,J=9.4 Hz, 1H), 7.89 (dd, J1=9.4 Hz, J2=0.9 Hz, 1H), 8.07 (d, J=0.9 Hz,1H), 14.09 (s, 1H)

Referential Example 41 Synthesis of4-formyl-2-(tetrahydropyran-2-yl)-5-trifluoromethanesulfonyloxy-2H-indazole(referential compound 41-1)

N-Phenylbis(trifluoromethanesulfonimide) (9.80 g, 27.4 mmol) and 15.0 ml(108 mmol) of triethylamine were added to a solution of 4.50 g (18.3mmol) of 4-formyl-5-hydroxy-2-(tetrahydropyran-2-yl)-2H-indazole(referential compound 40-1) in 100 ml of methylene chloride in an argonstream and the mixture was stirred at room temperature for 1 hour.

After the reaction was finished, water was added to the reactionsolution and the mixture was extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate and concentrated invacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=6:1 to 4:1(v/v)) and the fraction containing the aimed substance was concentratedin vacuo to give 6.00 g of the title compound as white powder (yield:87%).

Rf value: 0.30 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 379 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.60-1.90 (m, 3H),2.00-2.14 (m, 1H), 2.15-2.30 (m, 2H), 3.74-3.87 (m, 1H), 4.10-4.22 (m,1H), 5.70-5.80 (m, 1H), 7.30 (d, J=9.3 Hz, 1H), 8.12 (dd, J1=9.3 Hz,J2=1.0 Hz, 1H), 8.96 (d, J=1.0 Hz, 1H), 10.49 (s, 1H)

As hereunder, the referential compound 41-2 was produced in accordancewith the production process for the referential compound 41-1.

4-Methylcarbonyl-2-(tetrahydropyran-2-yl)-5-(trifluoromethanesulfonyloxy)-2H-indazole(referential compound 41-2)

Property: pale yellow oily substance Rf value: 0.74 (n-hexane:ethylacetate=1:1 (v/v)) Mass spectrum (CI, m/z): 393 (M⁺+1) ¹H-NMR spectrum(CDCl₃, δ ppm): 1.65-1.87 (m, 3H), 1.97-2.29 (m, 3H), 2.76 (s, 3H),3.74-3.85 (m, 1H), 4.10-4.18 (m, 1H), 5.67-5.73 (m, 1H), 7.26 (d, J=9.3Hz, 1H), 7.96 (dd, J1=9.3 Hz, J2=1.0 Hz, 1H), 8.65 (d, J=1.0 Hz, 1H)

Referential Example 42 Synthesis of 3-amino-2-methylanisole (referentialcompound 42-1)

A suspension of 9.98 g of 5% palladium-carbon (wet) in 100 ml of ethanolwas added to a solution of 30.7 g (184 mmol) of 2-methyl-3-nitroanisolein 300 ml of ethanol and the mixture was stirred for 3 hours at roomtemperature in a hydrogen atmosphere.

After the reaction was finished, the reaction solution was filteredthrough Celite and the filtrate was concentrated in vacuo to give 25.5 gof the title compound as a slightly purple oily substance (yield:quantitative).

Rf value: 0.38 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 137 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 2.04-2.05 (m, 3H), 3.60(brs, 2H), 3.80 (s, 3H), 6.33-6.37 (m, 2H), 6.94-7.01 (m, 1H)

As hereunder, the referential compounds 42-2 to 42-3 were produced inaccordance with the production process for the referential compound42-1.

3-Ethoxy-2-methylaniline (referential compound 42-2)

Rf value: 0.45 (n-hexane:ethyl acetate=5:1 (v/v)) Mass spectrum (EI,m/z): 151 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.40 (t, J=7.1 Hz, 3H),2.05 (s, 3H), 3.60 (brs, 2H), 4.00 (q, J=7.1 Hz, 2H), 6.28-6.36 (m, 2H),6.90-6.98 (m, 1H)

2-Methyl-3-n-propoxyaniline (referential compound 42-3)

Rf value: 0.41 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (EI,m/z): 165 (M⁺). ¹H-NMR spectrum (CDCl₃, δ ppm): 1.04 (t, J=7.3 Hz, 3H),1.74-1.87 (m, 2H), 2.06 (s, 3H), 3.59 (brs, 2H), 3.89 (t, J=6.3 Hz, 2H),6.31-6.35 (m, 2H), 6.90-6.98 (m, 1H)

Referential Example 43 Synthesis of 4-benzyloxy-1H-indazole (referentialcompound 43)

A 1N aqueous solution of sodium hydroxide (6.1 ml) was added to asolution of 500 mg (1.88 mmol) of 1-acetyl-4-benzyloxy-1H-indazole(referential compound 25-1) in 6.1 ml of methanol in an argon streamwith stirring and the mixture was stirred at room temperature for 30minutes.

After the reaction was finished, a 1N aqueous solution of hydrochloricacid was added to the reaction solution to neutralize it and the mixturewas concentrated in vacuo. The resulting residue was extracted with 50ml of ethyl acetate and the organic layer was successively washed with asaturated aqueous solution of sodium hydrogen carbonate and a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated in vacuo to give 397 mg of the title compoundas yellow solid (yield: 94%).

Rf value: 0.39 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 225 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 5.24 (s, 2H), 6.56 (d,J=7.6 Hz, 1H), 7.05-7.13 (m, 1H), 7.25-7.55 (m, 6H), 8.19 (d, J=1.0 Hz,1H), 10.10 (brs, 1H)

Referential Example 44 Synthesis of4-hydroxy-1-(tetrahydropyran-2-yl)-1H-indazole (referential compound 44)

Ethanol (27 ml) was added to 3.80 g (12.3 mmol) of4-benzyloxy-1-(tetrahydropyran-2-yl)-1H-indazole (referential compound28-4), then 1.9 g of 5% palladium-carbon (wet) was added thereto and themixture was stirred at room temperature for 2.5 hours in a hydrogenatmosphere.

After the reaction was finished, the reaction solution was filteredthrough Celite and the filtrate was concentrated in vacuo to give 2.99 gof the title compound as a colorless oily substance (yield:quantitative).

Rf value: 0.34 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 218 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.54-1.79 (m, 3H),2.04-2.19 (m, 2H), 2.45-2.60 (m, 1H), 3.70-3.78 (m, 1H), 4.01-4.07 (m,1H), 5.65-5.70 (m, 1H), 5.72 (brs, 1H), 6.47 (dd, J1=7.3 Hz, J2=0.7 Hz,1H), 7.12-7.16 (m, 1H), 7.22 (dd, J1=7.3 Hz, J2=7.2 Hz, 1H), 8.09 (d,J=0.7 Hz, 1H)

Referential Example 45 Synthesis of5-bromo-4-(2-chloroethyloxy)-1-(tetrahydropyran-2-yl)-1H-indazole(referential compound 45)

Potassium carbonate (1.04 g, 7.50 mmol) and 30 l ofN,N-dimethylformamide were added to 2.03 g (6.82 mmol) of5-bromo-4-hydroxy-1-(tetrahydropyran-2-yl)-1H-indazole (referentialcompound 26-5). After that, 1.70 ml (20.5 mmol) of1-bromo-2-chloroethane was added thereto in an argon stream withstirring and the mixture was stirred at 70° C. for 1.0 hour.

After the reaction was finished, the reaction solution was poured into200 ml of water and the mixture was extracted with 200 ml of toluene.The organic layer was successively washed with water and a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The resulting residue was subjectedto a silica gel column chromatography (eluting solvent: n-hexane:ethylacetate=5:1 (v/v)) and the fraction containing the aimed product wasconcentrated in vacuo to give 2.08 g of the title compound as brownsolid (yield: 85%).

Rf value: 0.67 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 358, 360 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.65-1.81 (m, 3H),2.05-2.25 (m, 2H), 2.47-2.58 (m, 1H), 3.70-3.78 (m, 1H), 3.88 (t, J=5.8Hz, 2H), 3.99-4.13 (m, 1H), 4.53 (t, J=5.8 Hz, 2H), 5.65-5.73 (m, 1H),7.23 (dd, J1=8.8 Hz, J2=0.9 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 8.13 (d,J=0.9 Hz, 1H)

Referential Example 46 Synthesis of5-bromo-1-(tetrahydropyran-2-yl)-4-vinyloxy-1H-indazole (referentialcompound 46)

A 50% aqueous solution (5.64 ml) of sodium hydroxide and 1.88 g (5.53mmol) of tetra-n-butylammonium hydrogen sulfate were added to a solutionof 1.99 g (5.53 mmol) of5-bromo-4-(2-chloroethyloxy)-1-(tetrahydropyran-2-yl)-1H-indazole(referential compound 45) in 47 ml of toluene in an argon stream withstirring and the mixture was stirred at room temperature for 2 hours.

After the reaction was finished, the reaction solution was poured into200 ml of water and the mixture was extracted with 200 ml of ethylacetate. The organic layer was successively washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=5:1 (v/v)) and the fraction containing the aimedproduct was concentrated in vacuo to give 1.41 g of the title compoundas white powder (yield: 79%).

Rf value: 0.72. (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 322, 324 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.63-1.84 (m, 3H),2.05-2.19 (m, 2H), 2.46-2.58 (m, 1H), 3.70-3.78 (m, 1H), 3.99-4.16 (m,1H), 4.45 (dd, J1=6.1 Hz, J2=2.4 Hz, 1H), 4.58 (dd, J1=13.8 Hz, J2=2.4Hz, 1H), 5.65-5.74 (m, 1H), 6.78 (dd, J1=13.8 Hz, J2=6.1 Hz, 1H), 7.27(dd, J1=9.0 Hz, J2=1.0 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 8.03 (d, J=1.0Hz, 1H)

Referential Example 47 Synthesis of5-bromo-4-cyclopropyloxy-1-(tetrahydropyran-2-yl)-1H-indazole(referential compound 47)

Chloroiodomethane (3.26 ml, 44.8 mmol) and 20.4 ml (22.4 mmol) ofdiethyl zinc were added to 1.13 g (3.50 mmol) of5-bromo-1-(tetrahydropyran-2-yl)-4-vinyloxy-1H-indazole (referentialcompound 46) in an argon stream with stirring and the mixture wasstirred at room temperature for 4.5 hours. After that, 3.26 ml (44.8mmol) of chloroiodomethane and 20.4 ml (22.4 mmol) of diethyl zinc wereadded thereto and further the mixture was stirred at room temperaturefor 15 hours.

After the reaction was finished, 200 ml of a saturated aqueous solutionof ammonium chloride was added to the reaction solution and the mixturewas extracted with 200 ml of toluene. The organic layer was successivelywashed with water and a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresulting residue was subjected to a silica gel column chromatography(eluting solvent: n-hexane:ethyl acetate=5:1 (v/v)) and the fractioncontaining the aimed product was concentrated in vacuo to give 0.95 g ofthe title compound as a pale yellow oily substance (yield: 80%).

Rf value: 0.65 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 336, 338 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.80-0.88 (m, 2H),0.91-1.05 (m, 2H), 1.58-1.85 (m, 3H), 2.09-2.19 (m, 2H), 2.49-2.62 (m,1H), 3.69-3.78 (m, 1H), 3.96-4.06 (m, 1H), 4.36-4.42 (m, 1H), 5.62-5.70(m, 1H), 7.13 (dd, J1=8.8 Hz, J2=0.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H),8.32 (d, J=0.8 Hz, 1H)

Referential Example 48 Synthesis of5-(1-aminocarbonylcyclopentyl)-2-bromopyridine (referential compound48-1)

Polyphosphoric acid (80 g) was added to 12 g (48 mmol) of2-bromo-5-(1-cyanocyclopentyl)pyridine (referential compound 1-6) andthe mixture was heated with stirring at 100° C. for 1.5 hours.

After the reaction was finished, 200 ml of toluene and 100 ml of waterwere successively added to the reaction solution and then potassiumcarbonate was added thereto to adjust pH of the aqueous layer to 7.After that, the resulting solid was filtered off, successively washedwith toluene and water and dried in vacuo to give 12 g of the titlecompound as white powder (yield: 93%).

Melting point: 211 to 212° C. Rf value: 0.10 (n-hexane:ethyl acetate=1:1(v/v)) Mass spectrum (CI, m/z): 269, 271 (M⁺+1) ¹H-NMR spectrum (CDCl₃,δ ppm): 1.65-2.05 (m, 6H), 2.40-2.60 (m, 2H), 5.25 (brs, 2H), 7.46 (dd,J1=8.4 Hz, J2=0.7 Hz, 2H), 7.57 (dd, J1=8.4 Hz, J2=2.7 Hz, 2H), 8.40(dd, J1=2.7 Hz, J2=0.7 Hz, 2H)

As hereunder, referential compound 48-2 was produced in accordance withthe production process for referential compound 48-1.

5-(17-Aminocarbonyl-1-ethylpropyl)-2-bromopyridine (referential compound48-2)

Rf value:, 0.42 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 271, 273 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.80 (t, J=7.4 Hz,6H), 1.95-2.07 (m, 4H), 5.17-5.38 (m, 2H), 7.47 (dd, J1=8.4 Hz, J2=0.8Hz, 1H), 7.51 (dd, J1=8.4 Hz, J2 2.6 Hz, 1H), 8.34 (dd, J1=2.6 Hz,J2=0.8 Hz, 1H)

Example 1 Synthesis of1-acetyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 1-1)

4-(1-tert-Butoxycarbonylamino-1-methylethyl)-1-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)benzene(referential compound 6-1) (1.26 g, 3.49 mmol), 792 mg (5.21 mmol) ofcesium fluoride, 400 mg (0.346 mmol) oftetrakis(triphenylphosphine)palladium and 20 ml of 1,2-dimethoxyethanewere added to 500 mg (1.74 mmol) of 1-acetyl-5-iodo-1H-indazole(referential compound 12-1) and the mixture was heated to reflux withstirring for 2 hours in an argon stream.

After the reaction was finished, the reaction solution was poured into50 ml of water and the mixture was extracted with 100 ml of ethylacetate. The organic layer was successively washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=5:1 (v/v)) and the fraction containing the aimedproduct was concentrated in vacuo to give 385 mg of the title compoundas white powder (yield: 56%).

Rf value: 0.48 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 394 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.40 (brs, 9H), 1.67(s, 6H), 2.81 (s, 3H), 4.98 (brs, 1H), 7.48-7.52 (m, 2H), 7.57-7.61 (m,2H), 7.80 (dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 7.91 (dd, J1=1.7 Hz, J2=0.8Hz, 1H), 8.17 (d, J=0.8 Hz, 1H), 8.46-8.50 (m, 1H)

As hereunder, the compounds 1-2 to 1-31 were produced in accordance withthe production process for the compound 1-1. Incidentally, in thesynthesis of the compounds 1-7 to 1-11, an adduct oftris(dibenzylideneacetone)dipalladium with chloroform was used insteadof tetrakis(triphenylphosphine)palladium and, in the synthesis of thecompounds 1-12 to 1-31, a 2M aqueous solution of sodium carbonate wasused instead of cesium fluoride.

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-methoxycarbonyl-1H-indazole(compound 1-2)

Rf value: 0.30 (n-hexane:ethyl acetate=2:1 (v/v)) ¹H-NMR spectrum(CDCl₃, δ ppm): 1.40 (brs, 9H), 1.68 (s, 6H), 1.76 (s, 9H), 4.06 (s,3H), 4.97 (brs, 1H), 7.48-7.52 (m, 2H), 7.61-7.65 (m, 2H), 7.83 (dd,J1=8.8 Hz, J2=1.7 Hz, 1H), 8.24 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 8.44(dd, J1=1.7 Hz, J2=0.7 Hz, 1H)

1-Acetyl-3-tert-butoxycarbonylamino-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 1-3)

Rf value: 0.29 (n-hexane:ethyl acetate=2:1 (v/v))

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-formyl-1H-indazole(compound 1-4)

Rf value: 0.48 (n-hexane:ethyl acetate=2:1 (v/v))

1-Acetyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-(1-methylvinyl)-1H-indazole(compound 1-5)

Rf value: 0.43 (n-hexane:ethyl acetate=4:1 (v/v))

1-Acetyl-6-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 1-6)

Rf value: 0.24 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 394 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.40 (brs, 1H), 1.68(s, 6H), 2.81 (s, 3H), 4.98 (brs, 1H), 7.48-7.53 (m, 2H), 7.61 (dd,J1=8.3 Hz, J2=1.5 Hz, 1H), 7.63-7.68 (m, 2H), 7.77 (dd, J1=8.3 Hz,J2=0.7 Hz, 1H), 8.14 (d, J=0.7 Hz, 1H), 8.67-8.69 (m, 1H)

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-nitro-1H-indazole(compound 1-7)

Rf value: 0.36 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (FAB,m/z): 496 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H), 1.67 (s,6H), 1.75 (s, 9H), 4.95 (brs, 1H), 7.31-7.34 (m, 2H), 7.46-7.51 (m, 2H),7.60 (d, J=8.7 Hz, 1H), 8.42(d, J=0.7 Hz, 1H), 8.45 (dd, J1=8.7 Hz,J2=0.7 Hz, 1H)

1-tert-Butoxycarbonyl-5-[4-(4-(tert-butoxycarbonylaminomethyl)phenyl]-4-nitro-1H-indazole(compound 1-8)

Rf value: 0.37 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (FAB,m/z): 469 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.48 (s, 9H), 1.74 (s,9H), 4.38-4.41 (m, 2H), 4.92 (brs, 1H), 7.31-7.40 (m, 4H), 7.58 (d,J=8.8 Hz, 1H), 8.44 (d, J=0.7 Hz, 1H), 8.47 (dd, J1=8.8 Hz, J2=0.7 Hz,1H)

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylaminocyclopentyl)phenyl]-4-nitro-1H-indazole(compound 1-9)

Rf value: 0.41 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (FAB,m/z): 522 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (brs, 9H), 1.75 (s,9H), 1.80-1.89 (m, 4H), 2.04-2.35 (m, 4H), 4.90 (brs, 1H), 7.28-7.33 (m,2H), 7.45-7.50 (m, 2H), 7.60 (d, J=8.5 Hz, 1H), 8.41-8.46 (m, 2H)

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-ethylpropyl)phenyl]-4-nitro-1H-indazole(compound 1-10)

Rf value: 0.50 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (FAB,m/z): 525 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.79 (t, J=7.3 Hz, 6H),1.41 (brs, 9H), 1.75 (s, 9H), 1.87-2.12 (m, 4H), 4.81 (brs, 1H), 7.32(d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.6 Hz, 1H), 8.43(d, J=0.8 Hz, 1H), 8.45 (dd, J1=8.6 Hz, J2=0.8 Hz, 1H)

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylaminoethyl)phenyl]-4-nitro-1H-indazole(compound 1-11)

Rf value: 0.50 (n-hexane:ethyl acetate=2:1 (v/v)) ¹H-NMR spectrum(DMSO-d₆, δ ppm): 1.31-1.45 (m, 12H), 1.68 (s, 9H), 4.63-4.75 (m, 1H),7.31-7.50 (m, 5H), 7.77 (d, J=8.6 Hz, 1H), 8.41 (dd, J1=8.6 Hz, J2=0.7Hz, 1H), 8.57 (d, J=0.7 Hz, 1H)

4-Benzyloxy-5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-1-(tetrahydropyran-2-yl)-1H-indazole(compound 1-12)

Rf value: 0.36 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 543 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H),1.68-1.82 (m, 9H), 2.06-2.22 (m, 2H), 2.50-2.65 (m, 1H), 3.69-3.81 (m,1H), 4.01-4.08 (m, 1H), 4.96 (brs, 1H), 5.31 (s, 2H), 5.69-5.74 (m, 1H),7.26-7.33 (m, 5H), 7.38 (dd, J1=8.8 Hz, J2=0.9 Hz, 1H), 7.67 (dd, J1=8.4Hz, J2=2.6 Hz, 1H), 7.85-7.91 (m, 2H), 8.09 (d, J=0.9 Hz, 1H), 8.75 (dd,J1=2.6 Hz, J2=0.9 Hz, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-nitro-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-13)

Rf value: 0.15 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 482 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H),1.59-1.84 (m, 9H), 2.04-2.28 (m, 3H), 3.78-3.86 (m, 1H), 4.11-4.18 (m,1H), 4.98 (brs, 1H), 5.73-5.77 (m, 1H), 7.42 (dd, J1=8.3 Hz, J2=1.0 Hz,1H), 7.48 (d, J=8.8 Hz, 1H), 7.79 (dd, J1=8.3 Hz, J2=2.4 Hz, 1H), 8.02(dd, J1=8.8 Hz, J2=1.0 Hz, 1H), 8.59-8.60 (m, 1H), 8.73 (dd, J1=2.4 Hz,J2=1.0 Hz, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)-3-chloropyridin-2-yl]-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-14)

Rf value: 0.27 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 470 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.40 (brs, 9H), 1.63-1.81(m, 9H), 2.04-2.28 (m, 3H), 3.75-3.84 (m, 1H), 4.11-4.16 (m, 1H), 5.01(brs, 1H), 5.68-5.73 (m, 1H), 7.65 (dd, J1=9.0 Hz, J2=1.7 Hz, 1H),7.76-7.81 (m, 2H), 8.06-8.08 (m, 1H), 8.24 (d, J=0.7 Hz, 1H), 8.63 (d,J=2.2 Hz, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-2-(tetrahydropyran-2-yl)-4-[2-(tetrahydropyran-2-yloxy)ethyl]-2H-indazole(compound 1-15)

Rf value: 0.36 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 564 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.06-1.85 (m, 23H),1.92-2.22 (m, 2H), 2.35-2.57 (m, 2H), 3.10-3.16 (m, 2H), 3.25-3.32 (m,1H), 3.43-3.63 (m, 2H), 3.69-3.93 (m, 3H), 4.42-4.47 (m, 1H), 5.81-5.87(m, 1H), 7.18 (brs, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.3 Hz, 2H),7.40 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.5 Hz, 1H), 8.22 (s, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridine-2-yl]-2-(tetrahydropyran-2-yl)-4-[(2-tetrahydropyran-2-yloxy)ethyl]-2H-indazole(compound 1-16)

Rf value: 0.13 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 565 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.06-1.85 (m, 23H),1.92-2.22 (m, 2H), 2.36-2.57 (m, 2H), 3.24-3.40 (m, 3H), 3.47-3.92 (m,5H), 4.44-4.49 (m, 1H), 5.84-5.89 (m, 1H), 7.32 (brs, 1H), 7.44 (d,J=8.8 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.78 (dd,J1=8.2 Hz, J2=2.4 Hz, 1H), 8.26 (s, 1H), 8.63 (d, J=2.4 Hz, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-formyl-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-17)

Property: white powder Rf value: 0.46 (n-hexane:ethyl acetate=1:1 (v/v))Mass spectrum (EI, m/z): 463 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.40(brs, 9H), 1.62-1.84 (m, 9H), 2.02-2.37 (m, 3H), 3.75-3.87 (m, 1H),4.11-4.19 (m, 1H), 4.98 (brs, 1H), 5.70-5.77 (m, 1H), 7.35-7.44 (m, 3H),7.48-7.54 (m, 2H), 8.02 (dd, J1=9.0 Hz, J2=0.9 Hz, 1H), 8.95 (d, J=0.9Hz, 1H), 10.06 (s, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-methylcarbonyl-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-18)

Property: pale yellow powder Melting point: 196 to 198° C. Rf value:0.46 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI, m/z): 477(M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (brs, 9H), 1.58-1.86 (m, 9H),1.94 (s, 3H), 2.01-2.35 (m, 3H), 3.74-3.83 (m, 1H), 4.10-4.17 (m, 1H),4.97 (brs, 1H), 5.66-5.71 (m, 1H), 7.33-7.39 (m, 3H), 7.45-7.51 (m, 2H),7.86 (dd, J1=8.8 Hz, J2=0.9 Hz, 1H), 8.42(d, J=0.9 Hz, 1H)

4-Benzyloxy-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-19)

Rf value: 0.40 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 541 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H), 1.60-1.80(m, 9H), 2.00-2.10 (m, 1H), 2.17-2.24 (m, 2H), 3.74-3.83 (m, 1H),4.11-4.15 (m, 1H), 4.85 (d, J=11.5 Hz, 1H), 4.90 (d, J=11.5 Hz, 1H),4.94 (brs, 1H), 5.64-5.68 (m, 1H), 7.17-7.30 (m, 5H), 7.33 (d, J=8.8 Hz,1H), 7.42-7.46 (m, 2H), 7.51 (dd, J1=8.8 Hz, J2=1.0 Hz, 1H), 7.54-7.58(m, 2H), 8.15 (d, J=1.0 Hz, 1H)

4-Benzyloxy-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1-(tetrahydropyran-2-yl)-1H-indazole(compound 1-20)

Rf value: 0.40 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 541 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39 (brs, 9H), 1.60-1.81(m, 9H), 2.04-2.17 (m, 2H), 2.51-2.63 (m, 1H), 3.73-3.80 (m, 1H),4.03-4.14 (m, 1H), 4.86 (brs, 1H), 4.97 )s, 2H), 5.68-5.73 (m, 1H),7.18-7.31 (m, 5H), 7.35 (dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 7.39-7.46 (m,3H), 7.51-7.55 (m, 2H), 8.07 (d, J=0.7 Hz, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-methoxy-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-21)

Rf value: 0.44 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 465 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H), 1.68-1.82(m, 9H), 2.04-2.26 (m, 3H), 3.76-3.84 (m, 4H), 4.13-4.18 (m, 1H), 4.94(brs, 1H), 5.66-5.71 (m, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.42-7.55 (m, 5H),8.30 (d, J=1.0 Hz, 1H)

4-Benzyloxy-5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-22)

Rf value: 0.31 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 543 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.34 (brs, 9H),1.51-1.83 (m, 9H), 1.95-2.12 (m, 2H), 2.20-2.35 (m, 1H), 3.69-3.79 (m,1H), 3.99-4.08 (m, 1H), 5.29 (d, J=11.2, 1H), 5.31 (d, J=11.2 Hz, 1H),5.73-5.79 (m, 1H), 7.26-7.45 (m, 6H), 7.63 (dd, J1=8.5 Hz, J2=2.4 Hz,1H), 7.71 (d, J=9.0 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 8.62 (d, J=2.4 Hz,1H), 8.82 (s, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-methoxy-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-23)

Rf value: 0.37 (n-hexane:ethyl acetate=1:2 (v/v)) Mass spectrum (CI,m/z): 467 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H),1.64-1.86 (m, 9H), 2.07-2.30 (m, 3H), 3.76-3.85 (m, 1H), 3.95 (s, 3H),4.14-4.19 (m, 1H), 4.96 (brs, 1H), 5.66-5.71 (m, 1H), 7.50 (dd, J1=9.0Hz, J2=0.9 Hz, 1H), 7.72 (dd, J1=8.3 Hz, J2=2.4 Hz, 1H), 7.77 (d, J=9.0Hz, 1H), 7.84 (dd, J1=8.3 Hz, J2=0.7 Hz, 1H), 8.33 (d, J=0.9 Hz, 1H),8.76 (dd, J1=2.4 Hz, J2=0.7 Hz, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-ethylpropyl)pyridin-2-yl]-4-methoxy-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-24)

Rf value: 0.20 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 495 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.82 (t, J=7.3 Hz, 6H),1.41 (brs, 9H), 1.69-1.81 (m, 3H), 1.90-2.35 (m, 7H), 3.76-3.84 (m, 1H),3.94 (s, 3H), 4.13-4.18 (m, 1H), 4.80 (brs, 1H), 5.65-5.72 (m, 1H), 7.50(dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 7.66 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H),7.81 (d, J=8.8 Hz, 1H), 7.86 (dd, J1=8.4 Hz, J2=0.7 Hz, 1H), 8.68 (d,J=0.7 Hz, 1H), 8.69 (dd, J1=2.4 Hz, J2=0.7 Hz, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-ethoxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 1-25)

Property: pale yellow powder Rf value: 0.13 (n-hexane:ethyl acetate=2:1(v/v)) Mass spectrum (CI, m/z): 481 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δppm): 1.33 (t, J=7.0 Hz, 3H), 1.39 (brs, 9H), 1.62-1.84 (m, 9H),2.03-2.22 (m, 2H), 2.50-2.64 (m, 1H), 3.71-3.81 (m, 1H), 4.01-4.09 (m,1H), 4.24 (q, J=7.0 Hz, 2H), 4.98 (brs, 1H), 5.68-5.73 (m, 1H), 7.34(dd, J1=8.8 Hz, J2=0.9 Hz, 1H), 7.72 (dd, J1=8.3 Hz, J2=2.6 Hz, 1H),7.90 (d, J=8.8 Hz, 1H), 7.91 (dd, J1=8.3 Hz, J2=0.7 Hz, 1H), 8.16 (d,J=0.9 Hz, 1H), 8.75 (dd, J1=2.6 Hz, J2=0.7 Hz, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-ethylpropyl)pyridin-2-yl]-4-ethoxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 1-26)

Rf value: 0.13 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 509 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.70 (t, J=7.1 Hz,6H), 1.30 (t, J=6.8 Hz, 3H), 1.35 (brs, 9H), 1.50-2.12 (m, 9H),2.35-2.55 (m, 1H), 3.71-3.80 (m, 1H), 3.80-3.95 (m, 1H), 4.35 (q, J=6.8Hz, 2H), 5.78-5.88 (m, 1H), 7.00 (brs, 1H), 7.40-7.47 (m, 1H), 7.67 (dd,J1=8.3 Hz, J2=2.2 Hz, 1H), 7.84-7.93 (m, 2H), 8.33 (s, 1H), 8.56 (d,J=2.2 Hz, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-n-propoxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 1-27)

Rf value: 0.34 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 495 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.94 (t, J=7.4 Hz, 3H),1.36 (brs, 9H), 1.63-1.81 (m, 11H), 2.04-2.19 (m, 2H), 2.51-2.64 (m,1H), 3.71-3.80 (m, 1H), 4.02-4.07 (m, 1H), 4.13 (t, J=6.5 Hz, 2H), 4.96(brs, 1H), 5.68-5.73 (m, 1H), 7.33 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 7.71(dd, J1=8.3 Hz, J2=2.4 Hz, 1H), 7.87-7.90 (m, 2H), 8.16 (d, J=0.7 Hz,1H), 8.75 (dd, J1=2.4 Hz, J2=0.9 Hz, 1H)

5-[5-(1-tert-Butoxycarbonylaminocyclopentyl)pyridin-2-yl]-4-methoxy-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-28)

Rf value: 0.33 (n-hexane:ethyl acetate=1:2 (v/v)) Mass spectrum (CI,m/z): 493 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (brs, 9H),1.66-1.91 (m, 8H), 2.07-2.30 (m, 6H), 3.74-3.85 (m, 1H), 3.94 (s, 3H),4.14-4.18 (m, 1H), 4.91 (brs, 1H), 5.66-5.71 (m, 1H), 7.50 (dd, J1=9.0Hz, J2=0.7 Hz, 1H), 7.73 (dd, J1=8.3 Hz, J2=2.4 Hz, 1H), 7.78 (d, J=9.0Hz, 1H), 7.84 (dd, J1=8.3 Hz, J2=1.0 Hz, 1H), 8.33 (d, J=0.7 Hz, 1H),8.75 (dd, J1=2.4 Hz, J2=1.0 Hz, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-cyclopropyloxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 1-29)

Rf value: 0.09 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 493 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.70-0.90 (m, 4H),1.34 (brs, 9H), 1.50-2.15 (m, 11H), 2.35-2.60 (m, 1H), 3.70-3.82 (m,1H), 3.83-3.95 (m, 1H), 4.42-4.48 (m, 1H), 5.80-5.88 (m, 1H), 7.26-7.29(m, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.65-7.75 (mi, 2H), 7.80 (d, J=8.5H,1H), 8.55 (s, 1H), 8.60(s, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-ethylpropyl)pyridin-2-yl]-4-cyclopropyloxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 1-30)

Rf value: 0.09 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 521 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.55-0.90 (m, 10H),1.35 (brs, 9H), 1.50-2.15 (m, 9H), 2.35-2.55 (m, 1H), 3.72-3.80 (m, 1H),3.89-3.99 (m, 1H), 4.42-4.48 (m, 1H), 5.83-5.86 (m, 1H), 6.99 (brs, 1H),7.42 (d, J=8.8 Hz, 1H), 7.64 (dd, J1=8.3 Hz, J2=2.4 Hz, 1H), 7.72 (d,J=8.3 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 8.50-8.60 (m, 2H)

4-Benzyloxy-5-[4-(1-tert-butoxycarbonylamino-1-ethylpropyl)phenyl]-1-(tetrahydropyran-2-yl)-1H-indazole(compound 1-31)

Rf value: 0.40 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 570 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.73 (t, J=7.3 Hz, 3H),0.80 (t, J=7.3 Hz, 3H), 1.41 (brs, 9H), 1.60-2.23 (m, 9H), 2.53-2.67 (m,1H), 3.73-3.83 (m, 1H), 4.03-4.12 (m, 1H), 4.80 (brs, 1H), 4.96 (s, 2H),5.70-5.77 (m, 1H), 7.15-7.28 (m, Si), 7.33-7.44 (m, 4H), 7.49-7.54 (m,2H), 8.10 (s, 1H)

Example 2 Synthesis of1-acetyl-5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-1H-indazole(compound 2)

1-Acetyl-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)-1H-indazole(referential compound 29-1) (414 mg, 1.45 mmol), 881 mg (5.80 mmol) ofcesium fluoride, 406 mg (0.580 mmol) ofdichlorobis(triphenylphosphine)palladium and 30 ml of1,2-dimethoxyethane were added to 463 mg (1.45 mmol) of2-bromo-5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridine(referential compound 4-4) and the mixture was heated to reflux withstirring an in argon stream for 4 hours.

After the reaction was finished, the reaction solution was poured into100 ml of water and the mixture was extracted with 300 ml of ethylacetate. The organic layer was successively washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=4:1 (v/v)) and the fraction containing the aimedproduct was concentrated in vacuo to give 155 mg of the title compoundas yellow powder (yield: 27%).

Rf value: 0.24 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 395 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (brs, 9H), 1.69(s, 6H), 2.81 (s, 3H), 5.00 (brs, 1H), 7.74 (dd, J1=8.3 Hz, J2=1.0 Hz,1H), 7.80 (dd, J1=8.3 Hz, J2=2.4 Hz, 1H), 8.19 (d, J=0.7 Hz, 1H), 8.20(dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 8.37-8.38 (m, 1H), 8.51 (ddd, J1=8.8 Hz,J2=0.7 Hz, J3=0.7 Hz, 1H), 8.77 (dd, J1=2.4 Hz, J2=1.0 Hz, 1H)

Example 3 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 3-1)

Tetrahydrofuran (5 ml), 5 ml of methanol and 0.5 ml of a 1N aqueoussolution of sodium hydroxide were added to 350 mg (0.89 mmol) of1-acetyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 1-1) and the mixture was stirred at room temperature for 10minutes.

After the reaction was finished, the reaction solution was poured into50 ml of water and the mixture was extracted with each 50 ml ofchloroform for three times. The organic layer was successively washedwith water and a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated in vacuo. Theresulting crystals were washed with 5 ml of methanol and 20 ml ofdiethyl ether to give 209 mg of the title compound as white powder(yield: 67%).

Rf value: 0.32 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 352 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.35 (brs, 9H), 1.53(s, 6H), 7.21 (brs, 1H), 7.40 (d, J=8.5 Hz, 2H), 7.59-7.63 (m, 3H), 7.66(dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 8.00 (dd, J1=1.7 Hz, J2=1.0 Hz, 1H),8.11 (d, J=1.0 Hz, 1H), 13.10 (brs, 1H)

As hereunder, the compounds 3-2 to 3-4 were produced in accordance withthe production process for the compound 3-1.

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-1H-indazole(compound 3-2)

Rf value: 0.17 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 353 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39 (brs, 9H), 1.69(s, 6H), 5.02 (brs, 1H), 7.51-7.55 (m, 1H), 7.67-7.71 (m, 1H), 7.76 (dd,J1=8.5 Hz, J2=2.4 Hz, 1H), 8.03-8.07 (m, 1H), 8.14 (d, J=1.0 Hz, 1H),8.35-8.36 (m, 1H), 8.75 (dd, J1=2.4 Hz, J2=0.7 Hz, 1H), 10.21 (brs, 1H)

3-tert-Butoxycarbonylamino-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 3-3)

Rf value: 0.10 (n-hexane:ethyl acetate=2:1 (v/v)) ¹H-NMR spectrum(CDCl₃, δ ppm): 1.39 (brs, 9H), 1.55 (s, 9H), 1.67 (s, 6H), 4.99 (brs,1H), 7.27-7.61 (m, 6H), 8.08-8.09 (m, 1H), 9.75 (brs, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-3-(1-methylvinyl)-1H-indazole(compound 3-4)

Rf value: 0.24 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 392 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39 (brs, 9H), 1.68(s, 6H), 2.35 (dd, J1=1.5 Hz, J2=0.7 Hz, 3H), 4.97 (brs, 1H), 5.53-5.56(m, 1H), 5.83-5.85 (m, 1H), 7.47-7.53 (m, 3H), 7.57-7.61 (m, 2H), 7.64(dd, J1=8.5 Hz, J2=1.5 Hz, 1H), 8.12-8.13 (m, 1H)

Example 4 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-methoxycarbonyl-1H-indazole(compound 4-1)

Tetrahydrofuran (2 ml), 2 ml of methanol and 0.2 ml of a 1N aqueoussolution of sodium hydroxide were added to 70 mg (0.14 mmol) of1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-methoxycarbonyl-1H-indazole(compound 1-2) and the mixture was stirred at room temperature for 30minutes.

After the reaction was finished, the reaction solution was poured into50 ml of chloroform and the mixture was successively washed with waterand a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultingresidue was subjected to a silica gel column chromatography (elutingsolvent: n-hexane:ethyl acetate=2:1 (v/v)) and the fraction containingthe aimed substance was concentrated in vacuo to give 51 mg of the titlecompound as white powder (yield: 91%).

Rf value: 0.24 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 410 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.42 (brs, 9H), 1.68(s, 6H), 4.07 (s, 3H), 5.05 (brs, 1H), 7.45-7.61 (m, 6H), 8.38-8.41 (m,1H), 11.09 (brs, 1H)

As hereunder, the compounds 4-2 to 4-3 were produced in accordance withthe production process for the compound 4-1.

5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-formyl-1H-indazole(compound 4-2)

Rf value: 0.45 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 380 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.44 (brs, 9H), 1.68(s, 6H), 5.12 (brs, 1H), 7.41-7.48 (m, 6H), 8.45-8.47 (m, 1H), 10.31 (s,1H), 11.26 (brs, 1H)

5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(pyrrol-1-yl)-1H-indazole(compound 4-3)

Rf value: 0.40 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 417 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H), 1.62(s, 6H), 4.91 (brs, 1H), 6.21 (dd, J1=2.2 Hz, J2=2.2 Hz, 2H), 6.72 (dd,J1=2.2 Hz, J2=2.2 Hz, 2H), 7.04-7.09 (m, 2H), 7.29-7.33 (m, 2H),7.46-7.53 (m, 2H), 8.06 (s, 1H), 10.23 (brs, 1H)

Example 5 Synthesis of 5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazoledihydrochloride (compound 5-1)

Methanol (4 ml) and 8 ml of a 4N hydrogen chloride/1,4-dioxane solutionwere added to 285 mg (0.63 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 3-1) and the mixture was stirred in argon stream at roomtemperature for 2.5 hours.

After the reaction was finished, the reaction solution was concentratedin vacuo. The resulting residue was dissolved in 1.5 ml of methanol, 10ml of 1,4-dioxane was added thereto and the resulting solid was filteredoff and washed with diethyl ether to give 130 mg of the title compoundas white powder (yield: 63%).

Melting point: 268 to 270° C. (decomposition) Rf value: 0.30(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 252 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H),7.62-7.66 (m, 3H), 7.69 (dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 7.77 (d, J=8.8Hz, 2H), 8.06 (dd, J1=1.7 Hz, J2=1.0 Hz, 1H), 8.14 (d, J=1.0 Hz, 1H),8.67 (brs, 3H)

As hereunder, the compounds 5-2 to 5-73 were produced in accordance withthe production process for the compound 5-1. In the synthesis of thecompound 5-15 however, a high performance liquid chromatography (elutingsolvent: 0.03 vol % aqueous solution of trifluoroaceticacid:acetonitrile=70:30 (v/v)) was used for separation and purification.In this case, the product was converted from a hydrochloride to atrifluoroacetate.

1-Acetyl-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole dihydrochloride(compound 5-2)

Melting point: 247 to 250° C. Mass spectrum (CI, m/z): 294 (M⁺+1) ¹H-NMRspectrum (DMSO-d₆, δ ppm): 1.66 (s, 6H), 2.75 (s, 3H), 7.66 (d, J=8.6Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 7.98 (dd, J1=8.8 Hz, J2=1.7 Hz, 1H),8.10 (brs, 3H), 8.21 (dd, J1=1.7 Hz, J2=0.7 Hz, 1H), 8.38-8.41 (m, 1H),8.53 (d, J=1.0 Hz, 1H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-1H-indazole trihydrochloride(compound 5-3)

Melting point: 271 to 273° C. (decomposition) Rf value: 0.31(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 253 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.72 (s, 6H),7.63-7.68 (m, 1H), 8.11-8.13 (m, 2H), 8.15 (dd, J1=8.8 Hz, J2=1.7 Hz,1H), 8.20 (d, J=1.0 Hz, 1H), 8.54 (dd, J1=1.7 Hz, J2=0.7 Hz, 1H), 8.72(brs, 3H), 8.85-8.86 (m, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-nitro-1H-indazolemonohydrochloride (compound 5-4)

Melting point: 255 to 261° C. (decomposition) Rf value: 0.33(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) IR spectrum(KBr, cm⁻¹): 1516, 1322 Mass spectrum (CI, m/z): 297 (M⁺+1) ¹H-NMRspectrum (DMSO-d₆, δ ppm): 1.69 (s, 6H), 7.47-7.51 (m, 3H), 7.65-7.68(m, 2H), 8.00 (dd, J1=8.5 Hz, J2=1.0 Hz, 1H), 8.31 (d, J=1.0 Hz, 1H),8.66 (brs, 3H), 13.93 (brs, 1H)

4-Amino-S-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole trihydrochloride(compound 5-5)

Melting point: 228 to 235° C. (decomposition) Rf value: 0.15(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 267 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.69 (s, 6H),6.82 (dd, J1=8.4 Hz, J2=0.9 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.53 (d,J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 8.27 (d, J=0.9 Hz, 1H), 8.60(brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-benzylamino-1H-indazoledihydrochloride (compound 5-6)

Melting point: 185 to 192° C. (decomposition) Rf value: 0.49(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 357 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H),4.59 (s, 2H), 6.82 (dd, J1=8.3 Hz, J2=1.0 Hz, 1H), 6.97 (d, J=8.3 Hz,1H), 7.16-7.31 (m, 5H), 7.50 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H),8.08 (d, J=1.0 Hz, 1H), 8.56 (brs, 3H), 12.82 (brs, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-methylamino-1H-indazoletrihydrochloride (compound 5-7)

Melting point: 202 to 206° C. (decomposition) Rf value: 0.33(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 281 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H),3.03 (s, 3H), 6.79 (d, J=8.3 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 7.47 (d,J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 8.29 (s, 1H), 8.53 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-3-methoxycarbonyl-1H-indazoledihydrochloride (compound 5-8)

Melting point: 264 to 267° C. (decomposition) Rf value: 0.49(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) IR spectrum(KBr, cm⁻¹): 1721 Mass spectrum (CI, m/z): 310 (M⁺+1) ¹H-NMR spectrum(DMSO-d₆, δ ppm): 1.68 (s, 6H), 3.95 (s, 3H), 7.66-7.69 (m, 2H),7.75-7.80 (m, 4H), 8.28-8.30 (m, 1H), 8.45 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-3-carboxy-1H-indazolemonohydrochloride (compound 5-9)

Melting point: 274 to 280° C. (decomposition) IR spectrum (KBr, cm⁻¹):1689 Mass spectrum (FAB, m/z): 296 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δppm): 1.68 (s, 6H), 7.66 (d, J=8.5 Hz, 2H), 7.76-7.80 (m, 4H), 8.30-8.31(m, 1H), 8.51 (brs, 3H), 13.90 (brs, 1H)

3-Aminocarbonyl-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazolemonohydrochloride (compound 5-10)

Melting point: 258 to 261° C. (decomposition) Rf value: 0.10(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) IR spectrum(KBr, cm⁻¹): 1664 Mass spectrum (CI, m/z): 295 (M⁺+1) ¹H-NMR spectrum(DMSO-d₆, δ ppm): 1.68 (s, 6H), 7.38 (brs, 1H), 7.66 (d, J=8.5 Hz, 2H),7.70 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 7.73-7.79 (m, 4H), 8.40 (brs, 3H),8.41-8.43 (m, 1H), 13.65 (brs, 1H)

3-Amino-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole trihydrochloride(compound 5-11)

Melting point: 220 to 222° C. (decomposition) Rf value: 0.10(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 267 (M⁺+1) ¹H-NMR spectrum (CD₃0D, δ ppm): 1.79 (s, 6H), 7.38(brs, 3H), 7.56 (d, J=8.8 Hz, 1H), 7.63-7.66 (m, 2H), 7.78-7.81 (m, 2H),7.99 (dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 8.25-8.26 (m, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-3-hydroxyiminomethyl-1H-indazolemonohydrochloride (compound 5-12)

Melting point: 227 to 230° C. (decomposition) Rf value: 0.21(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 295 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H),7.64-7.69 (m, 3H), 7.74 (d, J=8.5 Hz, 2H), 7.76 (dd, J1=8.8 Hz, J2=1.7Hz, 1H), 8.29-8.31 (m, 1H), 8.40 (s, 1H), 8.53 (brs, 3H), 11.44 (s, 1H),13.45 (brs, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-3-cyano-1H-indazole dihydrochloride(compound 5-13)

Melting point: 224 to 227° C. (decomposition) Rf value: 0.45(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) IR spectrum(KBr, cm⁻¹): 2241 Mass spectrum (CI, m/z): 277 (M⁺+1) ¹H-NMR spectrum(DMSO-d₆, δ ppm): 1.68 (s, 6H), 7.66 (d, J=8.5 Hz, 2H), 7.84-7.92 (m,4H), 8.14-8.15 (m, 1H), 8.61 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-3-hydroxymethyl-1H-indazoledihydrochloride (compound 5-14)

Melting point: 238 to 242° C. (decomposition) Rf value: 0.17(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 282 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H),4.83 (s, 2H), 7.57 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 7.64 (d, J=8.5 Hz,2H), 7.69 (dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 7.78 (d, J=8.5 Hz, 2H), 8.15(dd, J1=1.7 Hz, J2=0.7 Hz, 1H), 8.57 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-3-(1-methylvinyl)-1H-indazolemonotrifluoroacetate (compound 5-15)

Melting point: 221 to 225° C. (decomposition) Rf value: 0.43(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 292 (M⁺+1) ¹H-NMR spectrum (CD₃OD, δ ppm): 1.79 (s, 6H),2.31-2.33 (m, 3H), 5.43-5.45 (m, 1H), 5.80-5.83 (m, 1H), 7.58-7.63 (m,3H), 7.70 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.75-7.80 (m, 2H), 8.14 (dd,J1=1.6 Hz, J2=0.7 Hz, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-dimethylamino-1H-indazoletrihydrochloride (compound 5-16)

Melting point: 219 to 224° C. (decomposition) Rf value: 0.46(chloroform:methanol:28% aqueous ammonia 5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 295 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.69 (s, 6H),2.84 (s, 6H), 7.14 (d, J=8.5 Hz, 1H), 7.21-7.25 (m, 1H), 7.49 (d, J=8.5Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 8.34 (s, 1H), 8.64 (brs, 3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-nitro-1H-indazoledihydrochloride (compound 5-17)

Rf value: 0.40 (chloroform:methanol:28% aqueous ammonia=5:1:0.01(v/v/v)) Mass spectrum (CI, m/z): 298 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δppm): 1.73 (s, 6H), 7.72 (d, J=8.5 Hz, 1H), 7.85-7.88 (m, 1H), 8.02 (dd,J1=8.5 Hz, J2=1.0 Hz, 1H), 8.18 (dd, J1=8.5 Hz, J2=2.5 Hz, 1H), 8.30 (d,J=0.7 Hz, 1H), 8.75-8.85 (m, 4H)

4-(N-Acetylamino)-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazoledihydrochloride (compound 5-18)

Melting point: 218 to 221° C. Rf value: 0.09 (chloroform methanol:28%aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum (CI, m/z): 309 (M⁺+1)¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H), 1.99 (s, 3H), 7.33 (d,J=8.5 Hz, 1H), 7.47-7.53 (m, 3H), 7.61 (d, J=8.3 Hz, 2H), 7.91 (s, 1H),8.58-8.72 (m, 3H), 9.72 (brs, 1H)

5-[4-(Aminomethyl)phenyl]-4-nitro-1H-indazole dihydrochloride (compound5-19)

Melting point: 269 to 274° C. (decomposition) Rf value: 0.21(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 269 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 4.08-4.12 (m,2H), 7.44-7.48 (m, 3H), 7.59 (d, J=8.3 Hz, 2H), 8.00 (dd, J1=8.5 Hz,J2=1.0 Hz, 1H), 8.31 (d, J=1.0 Hz, 1H), 8.46 (brs, 3H)

4-Amino-5-[4-(aminomethyl)phenyl]-1H-indazole trihydrochloride (compound5-20)

Rf value: 0.08 (chloroform:methanol:28% aqueous ammonia=5:1:0.01(v/v/v)) Mass spectrum (EI, m/z): 238 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δppm): 4.04-4.08 (m, 2H), 6.90-6.94 (m, 1H), 7.06 (d, J=8.3 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 8.30 (d, J=1.0 Hz, 1H),8.48 (brs, 3H)

4-Amino-5-[4-(1-aminocyclopentyl)phenyl]-1H-indazole dihydrochloride(compound 5-21)

Melting point: 234 to 237° C. Rf value: 0.26 (chloroform:methanol:28%aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum (CI, m/z): 293 (M⁺+1)¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.75-2.03 (m, 4H), 2.16-2.28 (m, 4H),6.87-6.90 (m, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.63(d, J=8.5 Hz, 2H), 8.29 (d, J=1.0 Hz, 1H), 8.48-8.62 (m, 3H)

4-Amino-S-[4-(1-amino-1-ethylpropyl)phenyl]-1H-indazole trihydrochloride(compound 5-22)

Melting point: 197 to 199° C. (decomposition) Rf value: 0.35(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 295 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.83 (t, J=7.3Hz, 6H), 1.64-2.13 (m, 4H), 6.86-6.90 (m, 1H), 7.07 (d, J=8.5 Hz, 1H),7.48-7.56 (m, 4H), 8.30 (d, J=1.0 Hz, 1H), 8.55-8.70 (m, 3H)

5-[4-(Aminomethyl)phenyl]-4-dimethylamino-1H-indazole trihydrochloride(compound 5-23)

Melting point: 188 to 192° C. (decomposition) Rf value: 0.30(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 267 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 2.87 (s, 6H),4.05-4.08 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.20-7.30 (m, 1H), 7.48 (d,J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 8.33-8.55 (m, 4H)

5-[4-(1-Aminocyclopentyl)phenyl]-4-dimethylamino-1H-indazoletrihydrochloride (compound 5-24)

Melting point: 175 to 178° C. (decomposition) Rf value: 0.44(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(EI, m/z): 320 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.76-2.01 (m, 4H),2.16-2.28 (m, 4H), 2.85 (s, 6H), 7.14 (d, J=8.5 Hz, 1H), 7.20-7.27 (m,1H), 7.49 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 8.32-8.37 (m, 1H),8.50 (brs, 3H)

5-[4-(1-Amino-1-ethylpropyl)phenyl]-4-dimethylamino-1H-indazoletrihydrochloride (compound 5-25)

Rf value: 0.51 (chloroform:methanol:28% aqueous ammonia=5:1:0.01(v/v/v)) Mass spectrum (CI, m/z): 323 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δppm): 0.81 (t, J=7.3 Hz, 6H), 1.91-2.12 (m, 4H), 2.82 (s, 6H), 7.14-7.22(m, 2H), 7.44-7.52 (m, 4H), 8.29-8.33 (m, 1H), 8.55-8.68 (m, 3H)

5-[4-(1-Aminoethyl)phenyl]-4-dimethylamino-1H-indazole trihydrochloride(compound 5-26)

Melting point: 180 to 182° C. (decomposition) Rf value: 0.47(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(EI, m/z): 280 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.55 (d, J=6.8 Hz,3H), 2.79 (s, 6H), 4.39-4.52 (m, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.17 (d,J=8.4 Hz, 1H), 7.44-7.55 (m, 4H), 8.28 (s, 1H), 8.31 (brs, 3H)

5-[5-(1-Amino-1-methylethyl)-3-chloropyridin-2-yl]-1H-indazoletrihydrochloride (compound 5-27)

Melting point: 179 to 182° C. Rf value: 0.47 (chloroform:methanol:28%aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum (CI, m/z): 287 (M⁺+1)¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.73 (s, 6H), 7.62-7.70 (m, 2H),8.13-8.14 (m, 1H), 8.18 (d, J=0.7 Hz, 1H), 8.28 (d, J=2.2 Hz, 1H), 8.84(d, J=2.2 Hz, 1H), 8.85-8.98 (m, 3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-ethyl-1H-indazoletrihydrochloride (compound 5-28)

Melting point: 247 to 255° C. (decomposition) Rf value: 0.44(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 281 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.19 (t, J=7.6Hz, 3H), 1.78 (s, 6H), 2.97 (q, J=7.6 Hz, 2H), 7.39 (d, J=8.5 Hz, 1H),7.52 (dd, J1=8.5 Hz, J2=0.9 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 8.31 (d,J=0.9 Hz, 1H), 8.43-8.47 (m, 1H), 9.00-9.21 (m, 4H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-cyclopropyl-1H-indazoletrihydrochloride (compound 5-29)

Melting point: 209 to 213° C. (decomposition) Rf value: 0.47(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 293 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.47-0.53 (m,2H), 0.86-0.93 (m, 2H), 1.78 (s, 6H), 2.41-2.50 (m, 1H), 7.47 (d, J=8.5Hz, 1H), 7.52-7.56 (m, 1H), 8.02 (d, J=8.3 Hz, 1H), 8.25 (d, J=1.0 Hz,1H), 8.43-8.46 (m, 1H), 8.99-9.10 (m, 4H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-vinyl-1H-indazoletrihydrochloride (compound 5-30)

Melting point: 162 to 166° C. (decomposition) Rf value: 0.35(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 279 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.75 (s, 6H),5.59 (dd, J1=11.5 Hz, J2=1.2 Hz, 1H), 5.98 (dd, J1=17.8 Hz, J2=1.2 Hz,1H), 6.92 (dd, J1=17.8 Hz, J2=11.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.62(dd, J1=8.8 Hz, J2=0.9 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 8.26-8.29 (m,1H), 8.40 (d, J=0.9 Hz, 1H), 8.91-8.98 (m, 4H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-diethylamino-1H-indazoletrihydrochloride (compound 5-31)

Melting point: 182 to 184° C. (decomposition) Rf value: 0.51(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 323 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.78-1.04 (m,6H), 1.68 (s, 6H), 3.00-3.17 (m, 4H), 7.17 (d, J=8.5 Hz, 1H), 7.24-7.33(m, 1H), 7.39-7.74 (m, 4H), 8.21 (s, 1H), 8.50 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(2-hydroxyethyl)-1H-indazoledihydrochloride (compound 5-32)

Melting point: 202 to 203° C. (decomposition) Rf value: 0.11(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 296 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.70 (s, 6H),3.02 (t, J=7.4 Hz, 2H), 3.61 (t, J=7.4 Hz, 2H), 7.15 (d, J=8.5 Hz, 1H),7.41-7.47 (m, 3H), 7.65 (d, J=8.4 Hz, 2H), 8.18 (d, J=1.0 Hz, 1H), 8.68(brs, 3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-(2-hydroxyethyl)-1H-indazoletrihydrochloride (compound 5-33)

Rf value: 0.44 (chloroform:methanol:28% aqueous ammonia=5:1:0.01(v/v/v)) Mass spectrum (CI, m/z): 297 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δppm): 1.74 (s, 6H), 3.16 (t, J=7.1 Hz, 2H), 3.73 (t, J=7.1 Hz, 2H), 7.39(d, J=8.5 Hz, 1H), 7.49 (dd, J1=8.5 Hz, J2=1.0 Hz, 1H), 7.76 (d, J=8.3Hz, 1H), 8.12 (dd, J1=8.3 Hz, J2=2.4 Hz, 1H), 8.23 (d, J=1.0 Hz, 1H),8.59-8.82 (m, 3H), 8.86 (d, J=2.4 Hz, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(1-hydroxyethyl)-1H-indazoledihydrochloride (compound 5-34)

Property: white powder Rf value: 0.25 (chloroform:methanol:28% aqueousammonia=10:1:0.1 (v/v/v)) Mass spectrum (CI, m/z): 296 (M⁺+1) ¹H-NMRspectrum (DMSO-d₆, δ ppm): 1.43 (d, J=6.5 Hz, 3H), 1.70 (s, 6H), 4.95(q, J=6.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.45(dd, J1=8.5 Hz, J2=1.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 8.35 (d, J=1.0Hz, 1H), 8.65-8.81 (m, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-hydroxymethyl-1H-indazoledihydrochloride (compound 5-35)

Property: white powder Rf value: 0.18 (chloroform:methanol:28% aqueousammonia=10:1:0.1 (v/v/v)) Mass spectrum. (CI, m/z): 282 (M⁺+1) ¹H-NMRspectrum (DMSO-d₆, δ ppm): 1.70 (s, 6H), 4.68 (s, 2H), 7.25 (d, J=8.5Hz, 1H), 7.49-7.55 (m, 3H), 7.64 (d, J=8.5 Hz, 2H), 8.28 (d, J=1.0 Hz,1H), 8.59-8.77 (m, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-cyano-1H-indazolemonohydrochloride (compound 5-36)

Property: white powder Melting point: 270 to 272° C. Rf value: 0.38(chloroform:methanol:28% aqueous ammonia=10:1:0.1 (v/v/v)) Mass spectrum(CI, m/z): 277 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.71 (s, 6H),7.61 (d, J=8.8 Hz, 1H), 7.69-7.81 (m, 4H), 8.02 (d, J=8.8 Hz, 1H), 8.31(s, 1H), 8.68-8.85 (m, 3H), 13.85 (brs, 1H)

6-[4-(1-Amino-1-methylethyl)phenyl]-1H-indazole dihydrochloride(compound 5-37)

Melting point: 265 to 269° C. Rf value: 0.44 (chloroform:methanol:28%aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum (CI, m/z): 252 (M⁺+1)¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.69 (s, 6H), 7.44 (dd, J1=8.4 Hz,J2=1.5 Hz, 1H), 7.66-7.70 (m, 2H), 7.76-7.82 (m, 3H), 7.85 (dd, J1=8.4Hz, J2=0.7 Hz, 1H), 8.11 (d, J=1.0 Hz, 1H), 8.73 (brs, 3H)

1-Acetyl-6-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole dihydrochloride(compound 5-38)

Melting point: 225 to 230° C. Rf value: 0.64 (chloroform:methanol:28%aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum (CI, m/z): 294 (M⁺+1)¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.69 (s, 6H), 2.75 (s, 3H), 7.69-7.73(m, 2H), 7.76 (dd, J1=8.3 Hz, J2=1.7 Hz, 1H), 7.78-7.83 (m, 2H), 8,01(dd, J1=8.3 Hz, J2=0.7 Hz, 1H), 8.52 (d, J=0.7 Hz, 1H), 8.55-8.56 (m,1H), 8.60 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrrol-1-yl)-1H-indazoledihydrochloride (compound 5-39)

Melting point: 244 to 247° C. (decomposition) Rf value: 0.44(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 317 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.61 (s, 6H),6.18 (dd, J1=2.2 Hz, J2=2.0 Hz, 2H), 6.80 (dd, J1=2.2 Hz, J2=2.0 Hz,2H), 7.16-7.22 (m, 2H), 7.44-7.49 (m, 3H), 7.67 (dd, J1=8.5 Hz, J2=1.0Hz, 1H), 7.86-7.87 (m, 1H), 8.46 (brs, 3H), 13.47 (brs, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-isopropoxy-1H-indazoledihydrochloride (compound 5-40)

Melting point: 242 to 246° C. (decomposition) Rf value: 0.39(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 310 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.13 (d, J=6.1Hz, 6H), 1.68 (s, 6H), 4.52 (septet, J=6.1 Hz, 1H), 7.29 (dd, J1=8.5 Hz,J2=0.7 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.55-7.70 (m, 4H), 8.18 (d,J=0.7 Hz, 1H), 8.65 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(piperidin-1-yl)-1H-indazoletrihydrochloride (compound 5-41)

Melting point: 205 to 208° C. (decomposition) Rf value: 0.46(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 335 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.35-1.55 (m,6H), 1.68 (s, 6H), 3.00-3.12 (m, 4H), 7.14 (d, J=8.5 Hz, 1H), 7.19 (dd,J1=8.5 Hz, J2=0.7 Hz, 1H), 7.53-7.62 (m, 4H), 8.23 (d, J=0.7 Hz, 1H),8.61 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrrolidin-1-yl)-1H-indazoletrihydrochloride (compound 5-42)

Melting point: 218 to 224° C. (decomposition) Rf value: 0.44(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(EI, m/z): 320 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.67 (s, 6H),1.71-1.80 (m, 4H), 3.18-3.34 (m, 4H), 6.91 (d, J=8.2 Hz, 1H), 7.01 (d,J=8.2 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 8.30 (s,1H), 8.57 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(morpholin-4-yl)-1H-indazoletrihydrochloride (compound 5-43)

Melting point: 268 to 272° C. (decomposition) Rf value: 0.39(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 337 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H),3.05-3.11 (m, 4H), 3.50-3.68 (m, 4H), 7.17 (d, J=8.5 Hz, 1H), 7.25 (dd,J1=8.5 Hz, J2=0.8 Hz, 1H), 7.55-7.64 (m, 4H), 8.28 (d, J=0.8 Hz, 1H),8.55-8.67 (m, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-methoxy-1H-indazoledihydrochloride (compound 5-44)

Melting point: 258 to 261° C. (decomposition) Rf value: 0.34(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 282 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H),4.07 (s, 3H), 7.24 (dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 7.29 (d, J=8.5 Hz,1H), 7.53-7.62 (m, 4H), 8.37 (d, J=0.7 Hz, 1H), 8.61-8.73 (m, 3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-methoxy-1H-indazoletrihydrochloride (compound 5-45)

Melting point: 195 to 201° C. (decomposition) Rf value: 0.32(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 283 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.76 (s, 6H),4.26 (s, 3H), 7.31 (dd, J1=8.6 Hz, J2=1.0 Hz, 1H), 7.68 (d, J=8.6 Hz,1H), 8.14 (d, J=8.3 Hz, 1H), 8.39-8.47 (m, 1H), 8.52-8.53 (m, 1H), 8.95(d, J=2.2 Hz, 1H), 8.97-9.13 (m, 3H)

5-[5-(1-Aminocyclopentyl)pyridin-2-yl]-4-methoxy-1H-indazoletrihydrochloride (compound 5-46)

Melting point: 195 to 203° C. (decomposition) Rf value: 0.41(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 309 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.70-2.05 (m,4H), 2.20-2.37 (m, 4H), 4.26 (s, 3H), 7.31 (dd, J1=8.6 Hz, J2=1.0 Hz,1H), 7.69 (d, J=8.6 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.34-8.40 (m, 1H),8.52-8.53 (m, 1H), 8.79-8.95 (m, 4H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-ethoxy-1H-indazoletrihydrochloride (compound 5-47)

Property: yellow powder Melting point: 198 to 201° C. Rf value: 0.39(chloroform:methanol:28% aqueous ammonia=10:1:0.1 (v/v/v)) Mass spectrum(CI, m/z): 297 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.36 (t, J=6.9Hz, 3H), 1.77 (s, 6H), 4.58 (q, J=6.9 Hz, 2H), 7.32 (dd, J1=8.5 Hz,J2=1.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H),8.44-8.51 (m, 2H), 8.97 (d, J=2.4 Hz, 1H), 9.00-9.18 (m, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-hydroxy-1H-indazoledihydrochloride (compound 5-48)

Melting point: 194 to 198° C. (decomposition) Rf value: 0.12(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 268 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H),7.05 (dd, J1=8.5 Hz, J2=0.9 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.57 (d,J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 8.32 (d, J=0.9 Hz, 1H), 8.59(brs, 3H), 10.06 (brs, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-ethoxy-1H-indazole dihydrochloride(compound 5-49)

Melting point: 248 to 256° C. (decomposition) Rf value: 0.34(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 296 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.25 (t, J=7.0Hz, 3H), 1.68 (s, 6H), 4.32 (q, J=7.0 Hz, 2H), 7.26 (dd, J1=8.5 Hz,J2=1.0 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.52-7.70 (m, 4H), 8.28 (d,J=1.0 Hz, 1H), 8.62 (brs, 3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-isopropoxy-1H-indazoletrihydrochloride (compound 5-50)

Melting point: 211 to 213° C. (decomposition) Rf value: 0.39(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 311 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.22 (d, J=6.1Hz, 6H), 1.74 (s, 6H), 4.77-4.86 (m, 1H), 7.34 (dd, J1=8.7 Hz, J2=1.0Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.23-8.35 (m,2H), 8.87 (brs, 3H), 8.93 (d, J=2.2 Hz, 1H)

5-[5-(1-Amino-1-ethylpropyl)pyridin-2-yl]-4-methoxy-1H-indazoletrihydrochloride (compound 5-51)

Melting point: 204 to 206° C. (decomposition) Rf value: 0.41(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 311 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.85 (t, J=7.3Hz, 6H), 1.95-2.25 (m, 4H), 4.29 (s, 3H), 7.32 (d, J=8.8 Hz, 1H), 7.70(d, J=8.8 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 8.35-8.47 (m, 1H), 8.57 (s,1H), 8.87-8.94 (m, 1H), 9.00-9.24 (m, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-n-propoxy-1H-indazoledihydrochloride (compound 5-52)

Melting point: 237 to 243° C. (decomposition) Rf value: 0.41(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 310 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.89 (t, J=7.4Hz, 3H), 1.58-1.69 (m, 8H), 4.22 (t, J=6.5 Hz, 2H), 7.26 (dd, J1=8.5 Hz,J2=1.0 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.55-7.64 (m, 4H), 8.28 (d,J=1.0 Hz, 1H), 8.65 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-difluoromethoxy-1H-indazoledihydrochloride (compound 5-53)

Melting point: 227 to 230° C. (decomposition) Rf value: 0.32(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 318 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.69 (s, 6H),7.20 (t, ²J_(F-H)=73.6 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.54-7.70 (m,5H), 8.14 (d, 0.7 Hz, 1H), 8.63 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(2,2,2-trifluoroethoxy)-1H-indazoledihydrochloride (compound 5-54)

Rf value: 0.35 (chloroform:methanol:28% aqueous ammonia=5:1:0.01(v/v/v)) Mass spectrum (CI, m/z): 350 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δppm): 1.73 (s, 6H), 4.91 (q, ³J_(F-H)=9.0 Hz, 2H), 7.35 (d, J=8.5 Hz,1H), 7.39 (dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 7.55-65 (m, 4H), 8.33 (d,J=0.7 Hz, 1H), 8.60 (brs, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-n-butoxy-1H-indazoledihydrochloride (compound 5-55)

Melting point: 227 to 229° C. (decomposition) Rf value: 0.36(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(EI, m/z): 323 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.83 (t, J=7.3 Hz,3H), 1.27-1.39 (m, 2H), 1.55-1.65 (m, 2H), 1.67 (s, 6H), 4.24 (t, J=6.5Hz, 2H), 7.24-7.32 (m, 2H), 7.52-7.65 (m, 4H), 8.28 (s, 1H), 8.42-8.55(m, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(2-fluoroethoxy)-1H-indazoledihydrochloride (compound 5-56)

Rf value: 0.31 (chloroform:methanol:28% aqueous ammonia=5:1:0.01(v/v/v)) Mass spectrum (CI, m/z): 314 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δppm): 1.68 (s, 6H), 4.46-4.77 (m, 4H), 7.29 (dd, J1=8.5 Hz, J2=0.7 Hz,1H), 7.33 (d, J=8.5 Hz, 1H), 7.56-7.66 (m, 4H), 8.30 (d, J=0.7 Hz, 1H),8.50 (brs, 3H)

4-Allyloxy-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazoledihydrochloride (compound 5-57)

Melting point: 205 to 207° C. (decomposition) Rf value: 0.33(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 308 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H),4.83 (ddd, J1=5.1 Hz, J2=1.6 Hz, J3=1.5 Hz, 2H), 5.15 (ddd, J1=10.5 Hz,J2=3.4 Hz, J3=1.6 Hz, 1H), 5.30 (ddd, J1=17.1 Hz, J2=3.4 Hz, J3=1.5 Hz,1H), 5.92-6.05 (m, 1H), 7.24-7.34 (m, 2H), 7.55-7.66 (m, 4H), 8.29 (s,1H), 8.63 (brs, 3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-n-propoxy-1H-indazoletrihydrochloride (compound 5-58)

Melting point: 194 to 198° C. (decomposition) Rf value: 0.38(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 311 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.93 (t, J=7.3Hz, 3H), 1.68-1.80 (m, 8H), 4.46 (t, J=6.5 Hz, 2H), 7.33 (dd, J1=8.7 Hz,J2=1.0 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H),8.40-8.44 (m, 2H), 8.95-9.08 (m, 4H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-difluoromethoxy-1H-indazoletrihydrochloride (compound 5-59)

Melting point: 170 to 173° C. Rf value: 0.37 (chloroform:methanol:28%aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum (CI, m/z): 319 (M⁺+1)¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.73 (s, 6H), 7.31 (t, ²J_(F-H)=73.7Hz, 1H), 7.60 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H),7.88 (dd, J1=8.3 Hz, J2=0.7 Hz, 1H), 8.10 (dd, J1=8.3 Hz, J2=2.4 Hz,1H), 8.18 (d, J=0.7 Hz, 1H), 8.69 (brs, 3H), 8.90 (dd, J1=2.4 Hz, J2=0.7Hz, 1H)

5-[5-(1-Amino-1-ethylpropyl)pyridin-2-yl]-4-ethoxy-1H-indazoletrihydrochloride (compound 5-60)

Melting point: 200 to 202° C. (decomposition) Rf value: 0.49(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 325 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.85 (t, J=7.3Hz, 6H), 1.34 (t, J=7.0 Hz, 3H), 1.95-2.30 (m, 4H), 4.58 (q, J=7.0 Hz,2H), 7.33 (dd, J=8.8 Hz, J=0.9 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 8.26 (d,J=8.8 Hz, 1H), 8.40-8.55 (m, 2H), 8.92 (d, J=2.2 Hz, 1H), 9.00-9.25 (m,3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyridin-4-yl)-1H-indazoletrihydrochloride (compound 5-61)

Melting point: 266 to 269° C. (decomposition) Rf value: 0.31(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 329 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.62 (s, 6H),7.26 (d, J=8.3 Hz, 2H), 7.46-7.52 (m, 3H), 7.70-7.73 (m, 2H), 7.80 (dd,J1=8.8 Hz, J2=1.0 Hz, 1H), 7.95 (d, J=1.0 Hz, 1H), 8.59-8.70 (m, 3H),8.77 (dd, J1=5.1 Hz, J2=1.4 Hz, 2H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyridin-3-yl)-1H-indazoletrihydrochloride (compound 5-62)

Rf value: 0.32 (chloroform:methanol:28% aqueous ammonia=5:1:0.01(v/v/v)) Mass spectrum (CI, m/z): 329 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δppm): 1.59 (s, 6H), 7.24 (d, J=8.5 Hz, 2H), 7.42-7.47 (m, 3H), 7.54 (dd,J1=7.8 Hz, J2=5.0 Hz, 1H), 7.71 (dd, J1=8.8 Hz, J2=1.0 Hz, 1H), 7.85 (d,J=1.0 Hz, 1H), 7.90-7.94 (m, 1H), 8.44-8.50 (m, 4H), 8.58 (dd, J1=5.0Hz, J2=1.6 Hz, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyridin-2-yl)-1H-indazoletrihydrochloride (compound 5-63)

Melting point: 210 to 214° C. (decomposition) Rf value: 0.28(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 329 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.59 (s, 6H),7.15-7.24 (m, 3H), 7.36-7.63 (m, 4H), 7.69-7.75 (m, 2H), 7.87 (s, 1H),8.40-8.50 (m, 3H), 8.67-8.70 (m, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrazol-4-yl)-1H-indazoletrihydrochloride (compound 5-64)

Melting point: 259 to 267° C. (decomposition) Rf value: 0.15(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 318 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.66 (s, 6H),7.26-7.31 (m, 3H), 7.47-7.53 (m, 5H), 8.05 (d, J=1.2 Hz, 1H), 8.62 (brs,3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-(pyrazol-4-yl)-1H-indazoletetrahydrochloride (compound 5-65)

Rf value: 0.17 (chloroform:methanol:28% aqueous ammonia=5:1:0.01(v/v/v)) Mass spectrum (CI, m/z),: 319 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆,δ ppm): 1.71 (s, 6H), 7.35 (d, J=8.1 Hz, 1H), 7.48-7.59 (m, 4H),7.97-8.00 (m, 1H), 8.10 (d, J=1.0 Hz, 1H), 8.71-8.80 (m, 3H), 8.88 (d,J=2.4 Hz, 1H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(oxazol-5-yl)-1H-indazoledihydrochloride (compound 5-66)

Property: pale yellow powder Melting point: 212 to 214° C.(decomposition) Rf value: 0.27 (chloroform:methanol:28% aqueousammonia=10:1:0.1 (v/v/v)) Mass spectrum (CI, m/z): 319 (M⁺+1) ¹H-NMRspectrum (DMSO-d₆, δ ppm): 1.69 (s, 6H), 6.60 (s, 1H), 7.33 (d, J=8.7Hz, 1H), 7.36 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.68 (dd,J1=8.7 Hz, J2=1.0 Hz, 1H), 8.32 (d, J=1.0 Hz, 1H), 8.41 (s, 1H),8.61-8.78 (m, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrazol-3-yl)-1H-indazoletrihydrochloride (compound 5-67)

Property: yellow powder Rf value: 0.15 (chloroform:methanol:28% aqueousammonia=10:1:0.1 (v/v/v)) Mass spectrum (CI, m/z): 318 (M⁺+1) ¹H-NMRspectrum (DMSO-d₆, δ ppm): 1.66 (s, 6H), 5.90 (d, J=2.2 Hz, 1H), 7.28(d, J=8.4 Hz, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.62(dd, J1=8.5 Hz, J2=1.0 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 8.11 (d, J=1.0Hz, 1H), 8.66-8.82 (m, 3H)

5-[4-(1-Amino-1-methylethyl)phenyl]-4-(isoxazol-5-yl)-1H-indazoledihydrochloride (compound 5-68)

Property: pale yellow powder Melting point: 256 to 258° C.(decomposition) Rf value: 0.41 (chloroform:methanol:28% aqueousammonia=10:1:0.1 (v/v/v).) Mass spectrum (CI, m/z): 319 (M⁺+1) ¹H-NMRspectrum (DMSO-d₆, δ ppm): 1.68 (s, 6H), 6.24 (d, J=2.0 Hz, 1H),7.31-7.37 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.56-7.62 (m, 2H), 7.79 (dd,J1=8.5 Hz, J2=1.0 Hz, 1H), 8.21 (d, J=1.0 Hz, 1H), 8.59 (d, J=2.0 Hz,1H), 8.63-8.80 (m, 3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-hydroxy-1H-indazoletrihydrochloride (compound 5-69)

Melting point: 255 to 260° C. (decomposition) Rf value: 0.40(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 269 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.74 (s, 6H),7.08 (dd, J1=8.8 Hz, J2=0.9 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 8.21 (d,J=0.9 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.33 (dd, J1=8.8 Hz, J2=2.3 Hz,1H), 8.82 (d, J=2.3 Hz, 1H), 8.89-9.01 (m, 3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-cyclopropyloxy-1H-indazoletrihydrochloride (compound 5-70)

Melting point: 203 to 205° C. (decomposition) Rf value: 0.52(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 309 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.88-0.92 (m,4H), 1.76 (s, 6H), 4.53-4.56 (m, 1H), 7.31 (dd, J1=8.5 Hz, J2=0.9 Hz,1H), 7.65 (d, J=8.5 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.47-8.51 (m, 1H),8.65 (d, J=0.9 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 9.00-9.12 (m, 3H)

5-[5-(1-Amino-1-ethylpropyl)pyridin-2-yl]-4-cyclopropyloxy-1H-indazoletrihydrochloride (compound 5-71)

Melting point: 207 to 209° C. (decomposition) Rf value: 0.58(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 337 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.85-0.91 (m,10H), 1.85-2.31 (m, 4H), 4.50-4.59 (m, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.68(d, J=9.0 Hz, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.30-42 (m, 1H), 8.65 (s,1H), 8.80-8.95 (m, 1H), 8.91-9.20 (m, 3H)

5-[4-(1-Amino-1-ethylpropyl)phenyl]-4-difluoromethoxy-1H-indazoledihydrochloride (compound 5-72)

Melting point: 234 to 237° C. Rf value: 0.54 (chloroform :.methanol:28%aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum (CI, m/z): 346 (M⁺+1)¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.80 (dd, J1=7.3 Hz, J2=7.3 Hz, 6H),1.97 (dq, J1=15.1 Hz, J2=7.3 Hz, 2H), 2.10 (dq, J1=15.1 Hz, J2=7.3 Hz,2H), 7.14 (t, ²J_(F-H)=73.6 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.50-7.62(m, 5H), 8.13 (d, J=0.7 Hz, 1H), 8.59-8.76 (m, 3H)

5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-cyclopropylmethyloxy-1H-indazoletrihydrochloride (compound 5-73)

Melting point: 270 to 272° C. (decomposition) Rf value: 0.68(chloroform:methanol:28% aqueous ammonia=5:1:0.01 (v/v/v)) Mass spectrum(CI, m/z): 323 (M⁺+1) ¹H-NMR-spectrum (DMSO-d₆, δ ppm): 0.25-0.34 (m,2H), 0.45-0.53 (m, 2H), 1.11-1.26 (m, 1H), 1.78 (s, 6H), 4.35 (d, J=7.1Hz, 2H), 7.35 (dd, J1=8.5 Hz, J2=1.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H),8.32 (d, J=8.5 Hz, 1H), 8.45 (d, J=1.0 Hz, 1H), 8.55-8.65 (m, 1H), 9.01(d, J=2.2 Hz, 1H), 9.08-9.30 (m, 3H)

Example 6 Synthesis of4-amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 6-1)

1,4-Dioxane (10 ml) and 20 ml of ethanol were added to 336 mg (0.68mmol) of1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-nitro-1H-indazole(compound 1-7), then a suspension of 672 mg of 5% palladium-carbon (wet)in 10 ml of ethanol was added thereto and the mixture was stirred in ahydrogen atmosphere at room temperature for 1 hour.

After the reaction was finished, the reaction solution was filteredthrough Celite and the filtrate was concentrated in vacuo. The resultingresidue was subjected to a silica gel column chromatography (elutingsolvent: n-hexane:ethyl acetate=2:1 (v/v)) and the fraction containingthe aimed product was concentrated in vacuo to give 225 mg of the titlecompound as white powder (yield: 81%).

Rf value: 0.45 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (FAB,m/z): 466 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.40 (brs, 9H), 1.68(s, 6H), 1.73 (s, 9H), 4.98 (brs, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.40-7.43(m, 2H), 7.48-7.51 (m, 2H), 7.56 (d, J=8.5 Hz, 1H), 8.14 (s, 1H)

As hereunder, the compounds 6-2 to 6-5 were produced in accordance withthe production process for the compound 6-1.

4-Amino-1-tert-butoxycarbonyl-5-[4-(tert-butoxycarbonylaminomethyl)phenyl]-1H-indazole(compound 6-2)

Rf value: 0.32 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (FAB,m/z): 438 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.49 (s, 9H), 1.73 (s,9H), 4.25-4.40 (m, 4H), 4.92 (brs, 1H), 7.28 (d, J=8.5 Hz, AH),7.37-7.45 (m, 4H), 7.57 (dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 8.14 (d, J=0.7Hz, 1H)

4-Amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylaminocyclopentyl)phenyl]-1H-indazole(compound 6-3)

Rf value: 0.40 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (FAB,m/z): 492 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39 (brs, 9H), 1.73 (s,9H), 1.79-1.94 (m, 4H), 2.06-2.27 (m, 4H), 4.31 (brs, 2H), 4.91 (brs,1H), 7.30 (d, J=8.5 Hz, 1H), 7.38-7.42 (m, 2H), 7.47-7.51 (m, 2H),7.55-7.57 (m, 1H), 8.14 (d, J=0.7 Hz, 1H)

4-Amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-ethylpropyl)phenyl]-1H-indazole(compound 6-4)

Rf value: 0.22 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 494 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.80 (t, J=7.3 Hz, 6H),1.42 (brs, 9H), 1.73 (s, 9H), 1.90-2.14 (m, 4H), 4.29 (brs, 2H), 4.81(brs, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.38-7.45 (m, 4H), 7.55-7.58 (m, 1H),8.14 (d, J=0.7 Hz, 1H)

4-Amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylaminoethyl)phenyl]-1H-indazole(compound 6-5)

Rf value: 0.31 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (FAB,m/z): 452 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.30-1.47 (m, 12H),1.64 (s, 9H), 4.61-4.75 (m, 1H), 5.77 (brs, 2H), 7.19 (d, J=8.4 Hz, 1H),7.25-7.30 (m, 1H), 7.33-7.47 (m, 5H), 8.59 (d, J=0.7 Hz, 1H)

Example 7 Synthesis of4-benzylamino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 7)

A solution of 11 mg (0.10 mmol) of benzaldehyde in 1 ml of1,2-dichloroethane and a solution of 7.0 mg (0.12 mmol) of acetic acidin 1 ml of 1,2-dichloroethane were added to 47 mg (0.10 mmol) of4-amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 6-1) and then 28 mg (0.13 mmol) of sodiumtriacetoxyborohydride was added thereto. The mixture was stirred in anargon stream at room temperature for 1.5 hours, then 42 mg (0.20 mmol)of sodium triacetoxyborohydride was added thereto and the mixture wasstirred at room temperature for 17.5 hours.

After that, a solution of 11 mg (0.10 mmol) of benzaldehyde in 1 ml of1,2-dichloroethane, a solution of 7.0 mg (0.12 mmol) of acetic acid in 1ml of 1,2-dichloroethane and 42 mg (0.20 mmol) of sodiumtriacetoxyborohydride were added thereto and the mixture was stirred atroom temperature for 24 hours.

After the reaction was finished, the reaction solution was poured into20 ml of water and the mixture was neutralized with an aqueous solutionof sodium hydroxide and extracted with each 30 ml of ethyl acetatetwice. The organic layer was successively washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=6:1 (v/v)) and the fraction containing the aimedsubstance was concentrated in vacuo to give 28 mg of the title compoundas white powder (yield: 49%).

Rf value: 0.29 (n-hexane:ethyl acetate=2:1 (v/v)) ¹H-NMR spectrum(CDCl₃, δ ppm): 1.40 (brs, 9H), 1.66 (s, 6H), 1.70 (s, 9H), 4.69 (s,2H), 4.80-5.03 (m, 2H), 7.27-7.32 (m, 6H), 7.35-7.38 (m, 2H), 7.45-7.49(m, 2H), 7.58 (d, J=8.0 Hz, 1H), 8.08 (s, 1H)

Example 8 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-methylamino-1H-indazole(compound 8)

Ethyl orthoformate (2 ml) was added to 47 mg (0.10 mmol) of4-amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 6-1) and the mixture was stirred in an argon stream at 100° C.for 1 hour.

After that, the mixture was concentrated in vacuo, 3 ml of ethanol wasadded to the resulting residue, then 40 mg (1.1 mmol) of sodiumborohydride was added thereto and the mixture was stirred in an argonstream at room temperature for 17.5 hours. After that, 200 mg (5.3 mmol)of sodium borohydride was added thereto and the mixture was heated toreflux for 7 hours with stirring.

After the reaction was finished, the reaction solution was poured into50 ml of water and the mixture was extracted with 50 ml of chloroform.The organic layer was successively washed with water and a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The resulting residue was subjectedto a silica gel column chromatography (eluting solvent: n-hexane:ethylacetate=2:1 (v/v)) and the fraction containing the aimed substance wasconcentrated in vacuo to give 4.2 mg of the title compound as whitepowder (yield: 11%).

Rf value: 0.38 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 381 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.40 (brs, 9H), 1.68(s, 6H), 3.24 (s, 3H), 4.99 (brs, 1H), 6.82 (dd, J1=8.3 Hz, J2=0.8 Hz,1H), 7.11 (d, J=8.3 Hz, 1H), 7.34-7.38 (m, 2H), 7.45-7.48 (m, 2H), 8.29(d, J=0.8 Hz, 1H)

Example 9 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-carboxy-1H-indazole(compound 9)

Tetrahydrofuran (10 ml), 4 ml of methanol and 20 ml of a 1N aqueoussolution of sodium hydroxide were added to 120 mg (0.29 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-methoxycarbonyl-1H-indazole(compound 4-1) and the mixture was stirred at 75° C. for 7 hours.

After the reaction was finished, the reaction solution was poured into50 ml of a 10 weight % aqueous solution of citric acid and the mixturewas extracted with 200 ml of chloroform. The organic layer wassuccessively washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and concentratedin vacuo. The resulting crude crystals were washed with diethyl ether togive 21 mg of the title compound as white powder (yield: 18%).

Mass spectrum (CI, m/z): 396 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm):1.35 (brs, 9H), 1.54 (s, 6H), 7.22 (brs, 1H), 7.44 (d, J=8.4 Hz, 2H),7.61 (d, J=8.4 Hz, 2H), 7.70-7.80 (m, 2H), 8.27 (s, 1H), 12.96 (brs,1H), 13.82 (brs, 1H)

Example 10 Synthesis of3-aminocarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 10)

1,1′-Carbonyldiimidazole (11 mg, 0.068 mmol) and 2 ml of tetrahydrofuranwere added to 21 mg (0.053 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-carboxy-1H-indazole(compound 9) and the mixture was stirred in an argon stream at 45° C.for 30 minutes. After cooling it to room temperature, 2 ml of 28%aqueous ammonia was added thereto and the mixture was stirred at roomtemperature for 30 minutes.

After the reaction was finished, the reaction solution was poured into20 ml of a saturated aqueous solution of ammonium chloride and themixture was extracted with 30 ml of ethyl acetate. The organic layer wassuccessively washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and concentratedin vacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=1:1 (v/v)) andthe fraction containing the aimed substance was concentrated in vacuo togive 14 mg of the title compound as white powder (yield: 67%).

Rf value: 0.15 (n-hexane:ethyl acetate=1:1 (v/v)) ¹H-NMR spectrum(DMSO-d₆, δ ppm): 1.36 (brs, 9H), 1.53 (s, 6H), 7.21 (brs, 1H), 7.36(brs, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.59-7.74 (m, 5H), 8.37-8.38 (m, 1H),13.55 (brs, 1H)

Example 11 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-hydroxyiminomethyl-1H-indazole(compound 11-1)

A solution of 194 mg (1.50 mmol) of N,N-diisopropylethylamine in 1 ml ofethanol was added to a solution of 114 mg (0.300 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-formyl-1H-indazole(compound 4-2) in 25 ml of ethanol in an argon stream with stirring.After that, 83.0 mg (1.29 mmol) of hydroxylamine monohydrochloride wasadded thereto and the mixture was stirred at room temperature for 7hours.

After the reaction was finished, the reaction solution was concentratedin vacuo, 50 ml of saturated aqueous solution of ammonium chloride wasadded thereto and the mixture was extracted with 100 ml of ethylacetate. The organic layer was successively washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=2:1 (v/v)) and the fraction containing the aimedsubstance was concentrated in vacuo to give 105 mg of the title compoundas white powder (yield: 89%).

Rf value: 0.40 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 395 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.35 (brs, 9H), 1.53(s, 6H), 7.19 (brs, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.5 Hz, 2H),7.64 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 7.72 (dd, J1=8.8 Hz, J2=1.7 Hz,1H), 8.26-8.27 (m, 1H), 8.39 (s, 1H), 11.42 (s, 1H), 13.38 (brs, 1H)

As hereunder, the compound 11-2 was produced in accordance with theproduction process for the compound 11-1.

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)-phenyl]-4-hydroxyiminomethyl-2-(tetrahydropyran-2-yl)-2H-indazole(compound 11-2)

Rf value: 0.36 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 479 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39 (brs, 9H),1.63-1.85 (m, 9H), 2.02-2.13 (m, 1H), 2.18-2.31 (m, 2H), 3.76-3.85 (m,1H), 4.11-4.19 (m, 1H), 4.96 (brs, 1H), 5.68-5.73 (m, 1H), 7.25 (d,J=8.8 Hz, 1H), 7.29-7.35 (m, 2H), 7.43-7.50 (m, 2H), 7.79 (dd, J1=8.8Hz, J2=0.9 Hz, 1H), 8.30 (s, 1H), 8.71 (d, J=0.9 Hz, 1H)

Example 12 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-cyano-1H-indazole(compound 12-1)

A solution of 220 mg (1.7 mmol) of N,N-diisopropylethylamine

in 0.5 ml of tetrahydrofuran and a solution of 240 mg (1.1 mmol) oftrifluoroacetic anhydride in 0.5 ml of tetrahydrofuran were added to asolution of 45 mg (0.11 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-hydroxyiminomethyl-1H-indazole(compound 11-1) in 5 ml of tetrahydrofuran at 0° C. in an argon streamwith stirring. The mixture was stirred at 0° C. for 2 hours, a solutionof 100 mg (0.77 mmol) of N,N-diisopropylethylamine in 0.5 ml oftetrahydrofuran and a solution of 100 mg (0.48 mmol) of trifluoroaceticanhydride in 0.5 ml of tetrahydrofuran were added thereto and themixture was stirred at 0° C. for 1 hour. After that, 5 ml of 28% aqueousammonia was added thereto, a cooling bath was removed to warm up themixture gradually to room temperature.

After the reaction was finished, the reaction solution was poured into50 ml of a saturated aqueous solution of ammonium chloride and themixture was extracted with 50 ml of ethyl acetate. The organic layer wassuccessively washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and concentratedin vacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=2:1 (v/v)) andthe fraction containing the aimed substance was concentrated in vacuo togive 25 mg of the title compound as white powder (yield: 58%).

Rf value: 0.43 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 377 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.35 (brs, 9H), 1.54(s, 6H), 7.21 (brs, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H),7.81-7.88 (m, 2H), 8.06-8.07 (m, 1H)

As hereunder, the compound 12-2 was produced in accordance with theproduction process for the compound 12-1.

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-cyano-2-(tetrahydropyran-2-yl)-2H-indazole(compound 12-2)

Rf value: 0.55 (n-hexane:ethyl acetate=1:1 (v/v)) Mass. spectrum (EI,m/z): 460 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39 (brs, 9H),1.63-1.88 (m, 9H), 2.01-2.32 (m, 3H), 3.78-3.87 (m, 1H), 4.12-4.23 (m,1H), 4.97 (brs, 1H), 5.72-5.77 (m, 1H), 7.45 (d, J=9.0 Hz, 1H),7.50-7.64 (m, 4H), 7.98 (dd, J1=9.0 Hz, J2=0.9 Hz, 1H), 8.41 (d, J=0.9Hz, 1H)

Example 13 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-hydroxymethyl-1H-indazole(compound 13-1)

Sodium borohydride (2.0 mg, 0.053 mmol) was added to a solution of 11 mg(0.029 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-3-formyl-1H-indazole(compound 4-2) in 3 ml of ethanol in an argon stream with stirring andthe mixture was stirred at room temperature for 30 minutes.

After the reaction was finished, the reaction solution was concentratedin vacuo. Ethyl acetate (50 ml) was added to the residue, the mixturewas successively washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and concentratedin vacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=1:1 (v/v)) andthe fraction containing the aimed substance was concentrated in vacuo togive 10 mg of the title compound as white powder (yield: 91%).

Rf value: 0.32 (n-hexane:ethyl acetate=1:2 (v/v)) Mass spectrum (CI,m/z): 382 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.35 (brs, 9H), 1.53(s, 6H), 4.82 (d, J=5.6 Hz, 2H), 5.24 (t, J=5.6 Hz, 1H), 7.19 (brs, 1H),7.41 (d, J=8.5 Hz, 2H), 7.53-7.67 (m, 4H), 8.09-8.10 (m, 1H), 12.80(brs, 1H)

As hereunder, the compounds 13-2 to 13-3 were produced in accordancewith the production process for the compound 13-1.

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-hydroxymethyl-2-(tetrahydropyran-2-yl)-2H-indazole(compound 13-2)

Rf value: 0.74 (ethyl acetate) Mass spectrum (EI, m/z): 465 (M⁺) ¹H-NMRspectrum (CDCl₃, δ ppm): 1.39 (brs, 9H), 1.58-1.86 (m, 10H), 1.99-2.13(m, 1H), 2.18-2.30 (m, 2H), 3.75-3.86 (m, 1H), 4.12-4.20 (m, 1H), 4.89(d, J=5.4 Hz, 2H), 4.96 (brs, 1H), 5.68-5.73 (m, 1H), 7.25 (d, J=8.8 Hz,1H), 7.31-7.37 (m, 2H), 7.42-7.48 (m, 2H), 7.69 (dd, J1=8.8 Hz, J2=0.7Hz, 1H), 8.45 (d, J=0.7 Hz, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-(1-hydroxyethyl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 13-3)

Property: white powder Rf value: 0.29 (n-hexane:ethyl acetate=1:1 (v/v))Mass spectrum (EI, m/z): 479 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39(brs, 9H), 1.59 (d, J=5.1 Hz, 3H), 1.60-1.83 (m, 9H), 2.03-2.13 (m, 1H),2.18-2.33 (m, 2H), 3.73-3.82 (m, 1H), 4.13-4.19 (m, 1H), 4.96 (brs, 1H),5.19 (q, J=5.1 Hz, 1H), 5.65-5.72 (m, 1H), 7.12 (d, J=9.0 Hz, 1H),7.21-7.28 (m, 2H), 7.40-7.46 (m, 2H), 7.60-7.65 (m, 1H), 8.56 (d, J=0.7Hz, 1H)

Example 14 Synthesis of1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-dimethylamino-1H-indazole(compound 14-1)

A 38% aqueous solution of formaldehyde (4.00 ml, 50.6 mmol) and asuspension of 940 mg of 5% palladium-carbon (wet) in 10 ml of ethylacetate were added to a solution of 470 mg (1.01 mmol) of4-amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 6-1) in 60 ml of methanol and the mixture was stirred in ahydrogen atmosphere at room temperature for 4 hours.

After the reaction was finished, the reaction solution was filtered andthe filtrate was concentrated in vacuo. Ethyl acetate (200 ml) was addedto the resulting residue, the mixture was successively washed with waterand a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultingresidue was subjected to a silica gel column chromatography (elutingsolvent: n-hexane:ethyl acetate=4:1 (v/v)) and the fraction containingthe aimed substance was concentrated in vacuo to give 408 mg of thetitle compound as white powder (yield: 82%).

Rf value: 0.44 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 495 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H), 1.68(s, 6H), 1.73 (s, 9H), 2.81 (s, 6H), 4.94 (brs, 1H), 7.34-7.38 (m, 3H),7.41-7.45 (m, 2H), 7.75-7.78 (m, 1H), 8.35 (d, J=0.7 Hz, 1H)

As hereunder, the compounds 14-2 to 14-6 were produced in accordancewith the production process for the compound 14-1.

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylaminomethyl)phenyl]-4-dimethylamino-1H-indazole(compound 14-2)

Rf value: 0.55 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 466 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.48 (s, 9H), 1.73 (s,9H), 2.82 (s, 6H), 4.36-4.38 (m, 2H), 4.88 (brs, 1H), 7.30-7.35 (m, 3H),7.37-7.41 (m, 2H), 7.75-7.79 (m, 1H), 8.36 (d, J=1.0 Hz, 1H)

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylaminocyclopentyl)phenyl]-4-dimethylamino-1H-indazole(compound 14-3)

Rf value: 0.37 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 520 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.35 (brs, 9H), 1.72 (s,9H), 1.77-1.89 (m, 4H), 2.04-2.33 (m, 4H), 2.80 (s, 6H), 4.88 (brs, 1H),7.33-7.37 (m, 3H), 7.41-7.45 (m, 2H), 7.74-7.77 (m, 1H), 8.35 (d, J=0.7Hz, 1H)

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-ethylpropyl)phenyl]-4-dimethylamino-1H-indazole(compound 14-4)

Rf value: 0.48 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 522 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.78 (t, J=7.3 Hz, 6H),1.41 (brs, 9H), 1.73 (s, 9H), 1.90-2.16 (m, 4H), 2.80 (s, 6H), 4.80(brs, 1H), 7.35-7.38 (m, 5H), 7.74-7.78 (m, 1H), 8.35 (d, J=0.7 Hz, 1H)

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylaminoethyl)phenyl]-4-dimethylamino-1H-indazole(compound 14-5)

Rf value: 0.42 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (FAB,m/z): 480 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.30-1.44 (m, 12H),1.65 (s, 9H), 2.76 (s, 6H), 4.61-4.72 (m, 1H), 7.31-7.41 (m, 6H), 7.68(d, J=8.5 Hz, 1H), 8.56 (s, 1H)

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-diethylamino-1H-indazole(compound 14-6)

Rf value: 0.55 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 523 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.95 (t, J=7.1 Hz, 6H),1.38 (brs, 9H), 1.68 (s, 6H), 1.73 (s, 9H), 3.10 (q, J=7.1 Hz, 4H), 4.93(brs, 1H), 7.38 (d, J=8.9 Hz, 1H), 7.40-7.44 (m, 4H), 7.86 (d, J=8.9 Hz,1H), 8.28 (s, 1H)

Example 15 Synthesis of4-(N-acetylamino)-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 15)

Acetic acid (5 ml) and acetic anhydride (2.5 ml) were added to 238 mg(0.510 mmol) of4-amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 6-1) and the mixture was stirred at room temperature for 30minutes.

After the reaction was finished, the reaction solution was poured into100 ml of water and the mixture was extracted with 100 ml of ethylacetate. The organic layer was successively washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=1:1 (v/v)) and the fraction containing the aimedsubstance was concentrated in vacuo to give 254 mg of the title compoundas white powder (yield: 98%).

Rf value: 0.15 (n-hexane:ethyl acetate=1:2 (v/v)) Mass spectrum (FAB,m/z): 509 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.40 (brs, 9H), 1.68(s, 6H), 1.73 (s, 9H), 2.14 (s, 3H), 5.02 (brs, 1H), 7.18 (brs, 1H),7.31-7.36 (m, 2H), 7.45-7.53 (m, 3H), 8.08-8.12 (m, 1H), 8.21 (d, J=1.0Hz, 1H)

Example 16 Synthesis of5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)-pyridin-2-yl]-4-hydroxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 16-1)

Tetrahydrofuran (50 ml) and 100 ml of ethanol were added to 7.55 g (13.9mmol) of4-benzyloxy-5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-1-(tetrahydropyran-2-yl)-1H-indazole(compound 1-12), then suspension of 3.32 g of 5% palladium-carbon (wet)in 50 ml of ethanol was added thereto and the mixture was stirred in ahydrogen atmosphere at room temperature for 30 minutes.

After the reaction was finished, the reaction solution was filteredthrough Celite and the filtrate was concentrated in vacuo. The resultingresidue was dissolved in 20 ml of tetrahydrofuran, 200 ml of n-hexanewas added thereto and the resulting solid was filtered off to give 5.70g of the title compound as pale yellow powder (yield: 91%).

Rf value: 0.45 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 453 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (brs, 9H),1.60-1.85 (m, 9H), 2.05-2.20 (m, 2H), 2.51-2.63 (m, 1H), 3.70-3.79 (m,1H), 4.01-4.08 (m, 1H), 4.97 (brs, 1H), 5.65-5.70 (m, 1H), 7.06 (dd,J1=8.8 Hz, J2=0.7 Hz, 1H), 7.75-7.86 (m, 3H), 8.24 (d, J=0.7 Hz, 1H),8.52 (dd, J1=2.2 Hz, J2=1.0 Hz, 1H), 15.84 (brs, 1H)

As hereunder, the compounds 16-2 to 16-4 were produced in accordancewith the production process for the compound 16-1.

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-hydroxy-2-(tetrahydrofuran-2-yl)-2H-indazole(compound 16-2)

Rf value: 0.32 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 452 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.34 (brs, 9H),1.51-1.90 (m, 9H), 1.92-2.08 (m, 2H), 2.20-2.30 (m, 1H), 3.66-3.77 (m,1H), 3.93-4.10 (m, 1H), 5.67-5.73 (m, 1H), 7.11 (d, J=9.3 Hz, 1H), 7.35(brs, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.90 (dd, J1=8.8 Hz, J2=2.2 Hz, 1H),8.06 (d, J=8.8 Hz, 1H), 8.52 (d, J=2.2 Hz, 1H), 8.59 (s, 1H), 16.07(brs, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-hydroxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 16-3)

Rf value: 0.24 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 452 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.35 (brs, 9H),1.48-1.58 (m, 8H), 1.73-1.79 (m, 1H), 1.90-2.06 (m, 2H), 2.34-2.49 (m,1H), 3.68-3.77 (m, 1H), 3.87-3.92 (m, 1H), 5.73-5.78 (m, 1H), 7.12-7.21(m, 2H), 7.29-7.36 (m, 3H), 7.49 (d, J=8.5 Hz, 2H), 8.30 (s, 1H), 10.07(brs, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-ethylpropyl)-phenyl]-4-hydroxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 16-4)

Rf value: 0.20 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (CI,m/z): 480 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.61 (t, J=7.3 Hz,3H), 0.68 (t, J=7.3 Hz, 3H), 1.36 (brs, 9H), 1.52-2.10 (m, 9H),2.25-2.68 (m, 1H), 3.67-3.78 (m, 1H), 3.85-3.93 (m, 1H), 5.73-5.79 (m,1H), 6.79 (brs, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.30 (d, J=8.3 Hz, 2H),7.33 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.3 Hz, 2H), 8.29 (s, 1H), 9.11 (brs,1H)

Example 17 Synthesis of5-[5-(i-tert-butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-1-(tetrahydropyran-2-yl)-4-trifluoromethanesulfonyloxy-1H-indazole(compound 17-1)

A solution of 1.61 ml (9.57 mmol) of trifluoromethanesulfonic anhydridein 15 ml of methylene chloride was dropped in a solution of 2.26 g (4.99mmol) of5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-hydroxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 16-1) and 4.35 ml (23.9 mmol) of N,N-diisoproylethylamine in50 ml of methylene chloride at 0° C. during 30 minutes and the mixturewas stirred for 20 minutes.

After the reaction was finished, the reaction solution was poured into40 ml of a saturated aqueous solution of sodium hydrogen carbonate andthe mixture was extracted with 100 ml of chloroform. The organic layerwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated in vacuo. Theresulting residue was subjected to a silica gel column chromatography(eluting solvent: n-hexane:ethyl acetate=4:1 to 2:1 (v/v)) and thefraction containing the aimed substance was concentrated in vacuo togive 2.80 g of the title compound as slightly yellow foamy substance(yield: 96%).

Rf value: 0.41 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 585 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H),1.60-1.84 (m, 9H), 2.09-2.21 (m, 2H), 2.50-2.61 (m, 1H), 3.72-3.81 (m,1H), 3.99-4.05 (m, 1H), 5.01 (brs, 1H), 5.76-5.80 (m, 1H), 7.59 (d,J=8.5 Hz, 1H), 7.71 (dd, J1=8.7 Hz, J2=0.9 Hz, 1H), 7.77-7.82 (m, 2H),8.16 (s, 1H), 8.80 (dd, J1=2.6 Hz, J2=0.9 Hz, 1H)

As hereunder, the compounds 17-2 to 17-3 were produced in accordancewith the production process for the compound 17-1.

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-2-(tetrahydropyran-2-yl)-4-trifluoromethanesulfonyloxy-2H-indazole(compound 17-2)

Rf value: 0.32 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 583 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.34 (brs, 9H), 1.53(s, 6H), 1.60-1.80 (m, 3H), 1.95-2.02 (m, 1H), 2.06-2.12 (m, 1H),2.17-2.28 (m, 1H), 3.71-3.80 (m, 1H), 4.00-4.05 (m, 1H), 5.87-5.92 (m,1H), 7.23 (brs, 1H), 7.42-7.48 (m, 5H), 7.86 (dd, J1=8.9 Hz, J2=0.9 Hz,1H), 8.58-8.59 (m, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-2-(tetrahydropyran-2-yl)-4-trifluoromethanesulfonyloxy-2H-indazole(compound 17-3)

Rf value: 0.56 (n-hexane:ethyl acetate=1:2 (v/v)) Mass spectrum (CI,m/z): 585 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.09 (brs, 9H),1.44-1.80 (m, 9H), 1.89-2.36 (m, 3H), 3.67-3.78 (m, 1H), 3.95-4.10 (m,1H), 5.88-5.93 (m, 1H), 7.34 (brs, 1H), 7.65-7.72 (m, 2H), 7.81-7.91 (m,2H), 8.63 (s, 1H), 8.68 (d, J=2.0 Hz, 1H)

Example 18 Synthesis of5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-cyclopropyl-1-(tetrahydropyran-2-yl)-1H-indazole(compound 18-1)

Cyclopropylboronic-acid (206 mg, 2.40 mmol), 556 mg (2.40 mmol) ofsilver (I) oxide, 365 mg (2.40 mmol) of cesium fluoride, 185 mg (0.160mmol) of tetrakis(triphenylphosphine)palladium and 20 ml of1,2-dimethoxyethane were added to 468 mg (0.801 mmol) of5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-1-(tetrahydropyran-2-yl)-4-tri-fluoromethanesulfonyloxy-1H-indazole(compound 17-1) and the mixture was heated to reflux in an argon streamwith stirring for 30 minutes.

After the reaction was finished, the reaction solution was poured into100 ml of water and the mixture was extracted with 100 ml of ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue was subjected to a silicagel column chromatography (eluting solvent: n-hexane:ethyl acetate=3:1(v/v)) and the fraction containing the aimed substance was concentratedin vacuo to give 260 mg of the title compound as slightly orange powder(yield: 68%).

Rf value: 0.33 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 477 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 0.55-0.61 (m, 2H),0.82-0.90 (m, 2H), 1.37 (brs, 9H), 1.60-1.86 (m, 9H), 2.06-2.21 (m, 2H),2.30-2.36 (m, 1H), 2.54-2.65 (m, 1H), 3.70-3.79 (m, 1H), 4.02-4.06 (m,1H), 4.99 (brs, 1H), 5.70-5.75 (m, 1H), 7.46-7.57 (m, 3H), 7.74 (dd,J1=8.3 Hz, J2=2.6 Hz, 1H), 8.20 (s, 1H), 8.76 (dd, J1=2.6 Hz, J2=0.7 Hz,1H)

As hereunder, the compound 18-2 was produced in accordance with theproduction process for the compound 18-1.

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-1-(tetrahydropyran-2-yl)-4-vinyl-1H-indazole(compound 18-2)

Rf value: 0.37 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 463 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H),1.68-1.82 (m, 9H), 2.08-2.19 (m, 2H), 2.54-2.67 (m, 1H), 3.73-3.81 (m,1H), 4.02-4.06 (m, 1H), 4.99 (brs, 1H), 5.56 (dd, J1=11.2 Hz, J2=1.5 Hz,1H), 5.74-5.78 (m, 1H), 5.90 (dd, J1=17.8 Hz, J2=1.5 Hz, 1H), 6.96 (dd,J1=17.8 Hz, J2=11.2 Hz, 1H), 7.43 (dd, J1=8.3 Hz, J2=0.9 Hz, 1H), 7.57(d, J=9.0 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.73 (dd, J1 32 8.3 Hz,J2=2.4 Hz, 1H), 8.29 (s, 1H), 8.77 (dd, J1=2.4 Hz, J2=0.9 Hz, 1H)

Example 19 Synthesis of5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)-pyridin-2-yl]-4-ethyl-1-(tetrahydropyran-2-yl)-1H-indazole(compound 19)

A suspension of 80 mg of 5% palladium-carbon (wet) in 5 ml of ethanolwas added to a solution of 155 mg (0.335 mmol) of5-[5-(1-tert-butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-1-(tetrahydropyran-2-yl)-4-vinyl-1H-indazole(compound 18-2) in 10 ml of ethanol and the mixture was stirred in ahydrogen atmosphere at room temperature for 1 hour.

After the reaction was finished, the reaction solution was filtered andthe filtrate was concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:toluene:ethyl acetate=6:1 (v/v)) and the fraction containing the aimedsubstance was concentrated in vacuo to give 120 mg of the title compoundas white powder (yield: 77%).

Rf value: 0.38 (toluene:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 465 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.25 (t, J=7.6 Hz, 3H),1.38 (brs, 9H), 1.66-1.82 (m, 9H), 2.07-2.20 (m, 2H), 2.54-2.66 (m, 1H),3.02 (q, J=7.6 Hz, 2H), 3.72-3.80 (m, 1H), 4.02-4.07 (m, 1H), 4.98 (brs,1H), 5.71-5.76 (m, 1H), 7.36 (dd, J1=8.2 Hz, J2=0.9 Hz, 1H), 7.44 (d,J=8.9 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 7.75 (dd, J1=8.2 Hz, J2=2.6 Hz,1H), 8.12 (s, 1H), 8.75 (dd, J1=2.6 Hz, J2=0.9 Hz, 1H)

Example 20 Synthesis of1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(pyrrol-1-yl)-1H-indazole(compound 20)

Methanol (2.0 ml), 2.0 ml of acetic acid and 0.50 ml of2,5-dimethoxytetrahydrofuran were added to 20 mg (0.043 mmol) of4-amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 6-1) and the mixture was stirred at 60° C. for 30 minutes.

After the reaction was finished, the reaction solution was poured into20 ml of water, and the mixture was neutralized with a saturated aqueoussolution of sodium hydrogen carbonate and extracted with 50 ml of ethylacetate. The organic layer was successively washed with water and asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The resulting residue wassubjected to a silica gel column chromatography (eluting solvent:n-hexane:ethyl acetate=10:1 to 2:1 (v/v)) and the fraction containingthe aimed substance was concentrated in vacuo to give 23 mg of the titlecompound as yellow oily substance (yield: quantitative).

Rf value: 0.49 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 517 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (brs, 9H), 1.62(s, 6H), 1.75 (s, 9H), 4.90 (brs, 1H), 6.23 (dd, J1=2.2 Hz, J2=2.0 Hz,2H), 6.67 (dd, J1=2.2 Hz, J2=2.0 Hz, 2H), 7.03-7.08 (m, 2H), 7.30-7.34(m, 2H), 7.64 (d, J=8.5 Hz, 1H), 8.12 (d, J=0.7 Hz, 1H), 8.19 (dd,J1=8.5 Hz, J2=0.7 Hz, 1H)

Example 21 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-hydroxy-1H-indazole(compound 21)

1,4-Dioxane (15 ml) and 30 ml of ethanol were added to 2.17 g (4.01mmol) of4-benzyloxy-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-19), then a suspension of 1.00 g of 5% palladium-carbon(wet) in 10 ml of ethanol was added thereto and the mixture was stirredin a hydrogen atmosphere at room temperature for 8 hours.

After that, the reaction solution was filtered through Celite and thefiltrate was concentrated in vacuo. Tetrahydrofuran (30 ml) and 30 ml ofethanol were added to the resulting residue, then a suspension of 1.10 gof 5% palladium-carbon (wet) in 10 ml of ethanol was added thereto andthe mixture was stirred in a hydrogen atmosphere at room temperature for16 hours.

After the reaction was finished, the reaction solution was filteredthrough Celite and the filtrate was concentrated in vacuo. The resultingresidue was dissolved in tetrahydrofuran, n-hexane was added thereto andthe resulting solid was filtered off and washed with n-hexane to give1.14 g of the title compound as white powder (yield: 78%).

Rf value: 0.25 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 368 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.35 (brs, 9H), 1.53(s, 6H), 7.02 (dd, J1=8.4 Hz, J2=0.8 Hz, 1H), 7.14 (brs, 1H), 7.25 (d,J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 8.26-8.27(m, 1H), 9.88 (brs, 1H), 12.91 (brs, 1H)

Example 22 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-isopropoxy-1H-indazole(compound 22-1)

Potassium carbonate (289 mg, 2.09 mmol) and 5 ml ofN,N-dimethylformamide were added to 256 mg (0.697 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-hydroxy-1H-indazole(compound 21). After that, a solution of 118 mg (0.694 mmol) ofisopropyl iodide in 1 ml of N,N-dimethylformamide was added thereto withstirring in an argon stream and the mixture was stirred at roomtemperature for 18 hours.

After the reaction was finished, the reaction solution was poured into50 ml of water and the mixture was extracted with 50 ml of ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue was subjected to a silicagel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1(v/v)) and the fraction containing the aimed product was concentrated invacuo. The resulting crude crystals was dissolved in tetrahydrofuran,n-hexane was added thereto and the resulting solid was filtered off andwashed with n-hexane to give 173 mg of the title compound as slightlyorange powder (yield: 61%).

Rf value: 0.41 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 410 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.08 (d, J=6.1 Hz,6H), 1.34 (brs, 9H), 1.53 (s, 6H), 4.34-4.44 (m, 1H), 7.15 (brs, 1H),7.27 (dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.37 (d,J=8.5 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 8.12-8.14 (m, 1H), 13.10 (brs,1H)

As hereunder, the compounds 22-2 to 22-9 were produced in accordancewith the production process for the compound 22-1.

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-ethoxy-1H-indazole(compound 22-2)

Rf value: 0.37 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 395 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.23 (t, J=7.0 Hz, 3H),1.35 (brs, 9H), 1.53 (s, 6H), 4.25 (q, J=7.0 Hz, 2H), 7.16 (brs, 1H),7.24 (dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.36 (d,J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 8.24 (d, J=0.7 Hz, 1H), 13.12(brs, 1H)

5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-n-propoxy-1H-indazole(compound 22-3)

Rf value: 0.37 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 409 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.87 (t, J=7.4 Hz, 3H),1.35 (brs, 9H), 1.53-1.68 (m, 8H), 4.15 (t, J=6.3 Hz, 2H), 7.16 (brs,1H), 7.24 (dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.35(d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 8.23 (d, J=0.7 Hz, 1H), 13.12(brs, 1H)

4-n-Butoxy-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 22-4)

Rf value: 0.50 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 423 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.81 (t, J=7.3 Hz, 3H),1.00-1.45 (m, l1H), 1.53 (s, 6H), 1.55-1.65 (m, 2H), 4.17 (t, J=6.3 Hz,2H), 7.15 (brs, 1H), 7.22-7.31 (m, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.43 (d,J=8.4 Hz, 2H), 8.22 (s, 1H), 13.10 (brs, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-(2,2,2-trifluoroethoxy)-1H-indazole(compound 22-5)

Rf value: 0.43 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 533 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.34 (brs, 9H),1.46-1.87 (m, 9H), 1.93-2.13 (m, 2H), 2.30-2.50 (m, 1H), 3.67-3.80 (m,1H), 3.84-3.95 (m, 1H), 4.76 (q, ³J_(F-H)=8.8 Hz, 2H), 5.82-5.90 (m,1H), 7.18 (brs, 1H), 7.36-7.49 (m, 5H), 7.57 (d, J=8.5 Hz, 1H), 8.29 (s,1H)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-(2-fluoroethoxy)-1H-indazole(compound 22-6)

Rf value: 0.34 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 497 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.35 (brs, 9H),1.48-1.85 (m, 9H), 1.93-2,12 (m, 2H), 2.34-2.58 (m, 1H), 3.71-3.81 (m,1H), 3.87-3.94 (m, 1H), 4.35-4.75 (m, 4H), 5.82-5.87 (m, 1H), 7.17 (brs,1H), 7.35-7.42 (m, 3H), 7.45-7.51 (m, 3H), 8.29 (s, 1H)

4-Allyloxy-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 22-7)

Rf value: 0.51 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 407 (M⁺)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-isopropoxy-2-(tetrahydropyran-2-yl)-2H-indazole(compound 22-8)

Rf value: 0.27 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 495 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆): 1.13 (d, J=6.0 Hz, 3H), 1.15(d, J=6.0 Hz, 3H), 1.34 (bra, 9H), 1.50-1.80 (m, 9H), 1.90-2.16 (m, 2H),2.20-2.36 (m, 1H), 3.67-3.78 (m, 1H), 3.98-4.05 (m, 1H), 4.50-4.62 (m,1H), 5.71-5.77 (m, 1H), 7.29 (brs, 1H), 7.38 (dd, J1=8.8 Hz, J2=0.9 Hz,1H), 7.74-7.76 (m, 2H), 7.93 (d, J=8.3 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H),8.65 (d, J=0.9 Hz, 1H)

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-cyclopropylmethyloxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 22-9)

Rf value: 0.57 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 507 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆): 0.20-0.28 (m, 2H), 0.42-0.51(m, 2H), 1.12-1.40 (m, 10H), 1.56-1.63 (m, 8H), 1.69-1.84 (m, 1H),1.91-2.11 (m, 2H), 2.31-2.47 (m, 1H), 3.70-3.81 (m, 1H), 3.86-3.97 (m,1H), 4.10 (d, J=7.1 Hz, 2H), 5.81-5.86 (m, 1H), 7.30 (brs, 1H), 7.45(dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 7.73 (dd, J1=8.5 Hz, J2=2.7 Hz, 1H),7.87 (d, J=8.5 Hz, 1H), 7.96 (dd, J1=8.5 Hz, J=0.7 Hz, 1H), 8.30-8.31(m, 1H), 8.58-8.64 (m, 1H)

Example 23 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-hydroxy-2-(tetrahydropyran-2-yl)-2H-indazole(compound 23)

Pyridine (0.81 ml, 10.0 mol) and a suspension of 1.18 g of 5%palladium-carbon (wet) in 10 ml of ethanol were added to a solution of2.71 g (5.00 mmol) of4-benzyloxy-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-19) in 15 ml of tetrahydrofuran and 15 ml of ethanol and themixture was stirred in a hydrogen atmosphere at room temperature for 5hours. After that, a suspension of 600 mg of 5% palladium-carbon (wet)in 5 ml of ethanol was added thereto and the mixture was stirred in ahydrogen atmosphere at room temperature for 2 hours.

After the reaction was finished, the reaction solution was filteredthrough Celite, 100 ml of 10 weight % aqueous solution of citric acidwas added to the filtrate and the mixture was extracted with 300 ml ofethyl acetate. The organic layer was successively washed with water anda saturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated in vacuo to give 2.16 g of the titlecompound as slightly pink powder (yield: 96%).

Rf value: 0.30 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 451 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.36 (brs, 9H), 1.53(s, 6H), 1.57-1.80 (m, 3H), 1.90-1.99 (m, 1H), 2.07-2.15 (m, 2H),3.71-3.80 (m, 1H), 3.91-4.05 (m, 1H), 5.71-5.76 (m, 1H), 7.11-7.16 (m,2H), 7.22 (d, J=9.0 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz,2H), 8.58 (d, J=0.7 Hz, 1H), 9.71 (s, 1H)

Example 24 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(pyridin-4-yl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 24-1)

4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolanyl)pyridine (211 mg, 1.03mmol), 119 mg (0.103 mmol) of tetrakis(triphenylphosphine)palladium, 5ml of 1,2-dimethoxyethane and 2 ml of 2M aqueous solution of sodiumcarbonate were added to 300 mg (0.514 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-(tetrahydropyran-2-yl)-4-trifluoromethanesulfonyloxy-2H-indazole(compound 17-2) and the mixture was heated to reflux with stirring in anargon stream for 1 hours.

After the reaction was finished, the reaction solution was poured into50 ml of water and the mixture was extracted with 100 ml of ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue was subjected to a silicagel column chromatography (eluting solvent: n-hexane:ethyl acetate=2:1to 1:1 to 1:2 (v/v)) and the fraction containing the aimed product wasconcentrated in vacuo to give 236 mg of the title compound as slightlyorange powder (yield: 90%).

Rf value: 0.34 (n-hexane:ethyl acetate=1:2 (v/v)) Mass spectrum (CI,m/z): 513 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.35 (brs, 9H),1.58-1.85 (m, 9H), 2.04-2.27 (m, 3H), 3.74-3.82 (m, 1H), 4.11-4.15 (m,1H), 4.87 (brs, 1H), 5.64-5.69 (m, 1H), 7.09-7.13 (m, 2H), 7.20 (dd,J1=4.4 Hz, J2=1.7 Hz, 2H), 7.23-7.28 (m, 2H), 7.42 (d, J=9.0 Hz, 1H),7.80 (dd, J1=9.0 Hz, J2=1.0 Hz, 1H), 8.00-8.01 (m, 1H), 8.51 (dd, J1=4.4Hz, J2=1.7 Hz, 2H)

As hereunder, the compounds 24-2 to 24-3 were produced in accordancewith the production process for the compound 24-1.

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-(pyridin-3-yl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 24-2)

Rf value: 0.19 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 513 (M⁺+1)

5-[4-(1-tert-Butoxycarbonylamino-1-methylethyl)phenyl]-4-(pyridin-2-yl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 24-3)

Rf value: 0.29 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 513 (M⁺+1)

Example 25 Synthesis of1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(piperidin-1-yl)-1H-indazole(compound 25-1)

A suspension of 320 mg of 5% palladium-carbon (wet) in 3 ml of ethanoland 6.87 ml of a 50% aqueous solution of glutaraldehyde were added to asolution of 160 mg (0.343 mmol) of4-amino-1-tert-butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-1H-indazole(compound 6-1) in 30 ml of ethanol and the mixture was stirred in ahydrogen atmosphere at room temperature for 5 hours. After that, 3.44 mlof a 50% aqueous solution of glutaraldehyde was added thereto and themixture was stirred in a hydrogen atmosphere at room temperature for 2hours.

After the reaction was finished, the reaction solution was filteredthrough Celite and the filtrate was concentrated in vacuo. Water wasadded to the resulting residue and the resulting precipitate wasfiltered off and washed with water. The resulting powder was subjectedto a silica gel column chromatography (eluting solvent: n-hexane:ethylacetate=6:1 (v/v)) and the fraction containing the aimed product wasconcentrated in vacuo to give 163 mg of the title compound as a whitefoamy substance (yield: 89%).

Rf value: 0.38 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 535 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.27-1.54 (m, 15H),1.68 (s, 6H), 1.73 (s, 9H), 3.05-3.10 (m, 4H), 4.97 (brs, H), 7.35 (d,J=8.5 Hz, 1H), 7.40-7.45 (m, 4H), 7.79 (d, J=8.5 Hz, 1H), 8.34 (s, 1H)

As hereunder, the compounds 25-2 to 25-3 were produced in accordancewith the production process for the compound 25-1. Incidentally,succinaldehyde used for the synthesis of the compound 25-2 wassynthesized by referring to A. R. Katritzky, et al., J. Org. Chem., 65,3685 (2000). Similarly, oxy-bis-acetaldehyde used for the synthesis ofthe compound 25-3 was synthesized by referring to J-C. Florent, et al.,J. Med. Chem., 36, 1364 (1993).

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(pyrrolidin-1-yl)-1H-indazole(compound 25-2)

Rf value: 0.46 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 521 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (brs, 9H), 1.67(s, 6H), 1.72 (s, 9H), 1.77-1.82 (m, 4H), 3.23-3.28 (m, 4H), 4.94 (brs,1H), 7.25-7.40 (m, 5H), 7.58-7.62 (m, 1H), 8.41 (d, J=0.7 Hz, 1H)

1-tert-Butoxycarbonyl-5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(morpholin-4-yl)-1H-indazole(compound 25-3)

Rf value: 0.53 (n-hexane:ethyl acetate=1:1 (v/v)) ¹H-NMR spectrum(CDCl₃, δ ppm): 1.39 (s, 9H), 1.67 (s, 6H), 1.73 (s, 9H), 3.12-3.16 (m,4H), 3.56-3.63 (m, 4H), 4.97 (brs, 1H), 7.39 (d, J=8.8 Hz, 1H),7.42-7.48 (m, 4H), 7.89 (dd, J1=8.8 Hz, J2=0.7 Hz, 1H), 8.36 (d, J=0.7Hz, 1H)

Example 26 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-difluoromethoxy-1-(tetrahydro-pyran-2-yl)-1H-indazole(compound 26-1)

Cesium carbonate (1.47 g, 4.51 mmol) and 458 mg (3.00 mmol) of sodiumchlorodifluoroacetate were added to a solution of 680 mg (1.50 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-hydroxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 16-3) in 10 ml of N,N-dimethylformamide. The mixture wasstirred in an argon stream at 100° C. for 45 minutes.

After the reaction was finished, the reaction solution was poured into50 ml of water and the mixture was extracted with 50 ml of toluene. Theorganic layer was successively washed with water and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue was subjected to a silicagel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1(v/v)) and the fraction containing the aimed product was concentrated invacuo to give 343 mg of the title compound as white powder (yield: 46%).

Rf value: 0.46 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (EI,m/z): 501 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.35 (brs, 9H),1.48-1.85 (m, 9H), 1.95-2.12 (m, 2H), 2.34-2.57 (m, 1H), 3.72-3.82 (m,1H), 3.86-3.94 (m, 1H), 5.89-5.95 (m, 1H), 7.10 (t, ²J_(F-H)=74.0 Hz,1H), 7.18 (brs, 1H), 7.37-7.48 (m, 4H), 7.49 (d, J=8.8 Hz, 1H), 7.75 (d,J=8.8 Hz, 1H), 8.15 (s, 1H)

As hereunder, the compounds 26-2 to 26-3 were produced in accordancewith the production process for the compound 26-1.

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-difluoromethoxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 26-2)

Rf value: 0.29 (n-hexane:ethyl acetate=2:1 (v/v)) Mass spectrum (CI,m/z): 503 (M⁺+1) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 1.34 (brs, 9H),1.50-1.86 (m, 9H), 1.96-2.12 (m, 2H), 2.34-2.53 (m, 1H), 3.72-3.83 (m,1H), 3.86-3.95 (m, 1H), 5.89-5.96 (m, 1H), 7.26 (t, ²J_(F-H)=74.0 Hz,1H), 7.33 (brs, 1H), 7.72 (dd, J1=8.5 Hz, J2=0.7 Hz, 1H), 7.76-7.88 (m,3H), 8.18 (s, 1H), 8.66 (dd, J1=2.4 Hz, J2=0.7 Hz, 1H)

5-[4-(1-tert-Butoxycarbonylamino-1-ethylpropyl)phenyl]-4-difluoromethoxy-1-(tetrahydropyran-2-yl)-1H-indazole(compound 26-3)

Rf value: 0.40 (n-hexane:ethyl acetate=4:1 (v/v)) Mass spectrum (EI,m/z): 529 (M⁺) ¹H-NMR spectrum (DMSO-d₆, δ ppm): 0.68 (t, J=7.3 Hz, 6H),1.35 (brs, 9H), 1.55-1.65 (m, 2H), 1.70-1.90 (m, 3H), 1.92-2.12 (m, 4H),2.34-2.57 (m, 1H), 3.71-3.83 (m, 1H), 3.85-3.95 (m, 1H), 5.87-5.97 (m,1H), 6.81 (brs, 1H), 7.04 (t, ²J_(F-H)=73.6 Hz, 1H), 7.36 (d, J=8.5 Hz,2H), 7.44 (d, J=8.5 Hz, 2H), 7.51 (d, J=8.7 Hz, 1H), 7.76 (d, J=8.7 Hz,1H), 8.15 (s, 1H)

Example 27 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(pyrazol-4-yl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 27-1)

1-tert-Butoxycarbonyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolanyl)pyrazole(312 mg, 1.06 mmol), 123 mg (0.106 mmol) of tetrakistriphenylphosphinepalladium, 5 ml of 1,2-dimethoxyethane and 2 ml of 2M aqueous solutionof sodium carbonate were added to 310 mg (0.531 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-(tetrahydropyran-2-yl)-4-trifluoromethanesulfonyloxy-2H-indazole(compound 17-2) and the mixture was heated to reflux in an argon streamfor 30 minutes with stirring. After the mixture was cooled down to roomtemperature, 5 ml of methanol and 1 ml of 1N sodium hydroxide solutionwere added thereto and the mixture was stirred at room temperature for30 minutes.

After the reaction was finished, the reaction solution was poured into asaturated aqueous solution of ammonium chloride and the mixture wasextracted with ethyl acetate. The organic layer was successively washedwith water and a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated in vacuo. Theresulting residue was subjected to a silica gel column chromatography(eluting solvent: n-hexane:ethyl acetate=1:1 (v/v)) and the fractioncontaining the aimed product was concentrated in vacuo to give 215 mg ofthe title compound as slightly yellow powder (yield: 81%).

Rf value: 0.20 (n-hexane:ethyl acetate=1:2 (v/v)) Mass spectrum (CI,m/z): 502 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.38 (brs, 9H),1.64-1.83 (m, 9H), 2.04-2.25 (m, 3H), 3.74-3.83 (m, 1H), 4.11-4.16 (m,1H), 4.95 (brs, 1H), 5.66-5.71 (m, 1H), 7.17-7.22 (m, 2H), 7.30-7.35 (m,3H), 7.40-7.42 (m, 2H), 7.69 (dd, J1=8.9 Hz, J2=1.1 Hz, 1H), 8.20-8.21(m, 1H)

As hereunder, the compound 27-2 was produced in accordance with theproduction process for the compound 27-1.

5-[5-(1-tert-Butoxycarbonylamino-1-methylethyl)pyridin-2-yl]-4-(pyrazol-4-yl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 27-2)

Rf value: 0.22 (ethyl acetate) Mass spectrum (CI, m/z): 503 (M⁺+1)¹H-NMR spectrum (CDCl₃, δ ppm): 1.37 (brs, 9H), 1.65-1.80 (m, 9H),2.04-2.25 (m, 3H), 3.75-3.83 (m, 1H), 4.11-4.16 (m, 1H), 4.98 (brs, 1H),5.66-5.71 (m, 1H), 7.08 (d, J=8.3 Hz, 1H), 7.46-7.57 (m, 4H), 7.73 (dd,J1=9.0 Hz, J2=1.0 Hz, 1H), 8.18-8.20 (m, 1H), 8.72 (d, J=1.7 Hz, 1H)

Example 28

Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(oxazol-5-yl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 28)

(p-toluenesulfonyl)methyl isocyanide (200 mg, 1.02 mmol) and 150 mg(1.09 mmol) of potassium carbonate were added in an argon stream to asolution of 398 mg (0.858 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)]phenyl]-4-formyl-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-17) in 5 ml of methanol and the mixture was heated to refluxwith stirring for 1.5 hours.

After the reaction was finished, the reaction solution was concentratedin vacuo. The resulting residue was subjected to a silica gel columnchromatography (eluting solvent: n-hexane:ethyl acetate=2:1 to 1:1(v/v)) and the fraction containing the aimed product was concentrated invacuo to give 139 mg of the title compound as pale yellow powder (yield:32%).

Rf value: 0.29 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (EI,m/z): 502 (M⁺) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39 (brs, 9H), 1.62-1.85(m, 9H), 2.02-2.14 (m, 1H), 2.20-2.31 (m, 2H), 3.77-3.88 (m, 1H),4.13-4.21 (m, 1H), 4.95 (brs, 1H), 5.71-5.76 (m, 1H), 6.34 (s, 1H),7.23-7.32 (m, 3H), 7.42-7.49 (m, 2H), 7.75 (dd, J1=8.8 Hz, J2=1.0 Hz,1H), 7.90 (s, 1H), 8.56 (d, J=1.0 Hz, 1H)

Example 29 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(3-dimethylaminoacryloyl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 29)

N,N-Dimethylformamide dimethylacetal (2.0 ml, 15 mmol) was added to asolution of 500 mg (1.05 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)]phenyl]-4-methylcarbonyl-2-(tetrahydropyran-2-yl)-2H-indazole(compound 1-18) in 6 ml of N,N-dimethylformamide in an argon stream andthe mixture was stirred at 70° C. for 1.5 hours and then at 100° C. for4 hours.

After the reaction was finished, the reaction solution was concentratedin vacuo, the resulting residue was subjected to a silica gel columnchromatography (eluting solvent: ethyl acetate) and the fractioncontaining the aimed′substance was concentrated in vacuo. The resultingresidue was recrystallized from chloroform/ethyl acetate/n-hexane andfiltered off to give 450 mg of the title compound as yellow powder(yield: 81%).

Melting point: 191 to 194° C. Rf value: 0.22 (ethyl acetate) Massspectrum (CI, m/z): 533 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39(brs, 9H), 1.59-1.82 (m, 9H), 1.97-2.11 (m, 1H), 2.14-2.30 (m, 2H), 2.45(brs, 3H), 2.90 (brs, 3H), 3.73-3.83 (m, 1H), 4.08-4.19 (m, 1H),4.71-4.80 (m, 1H), 4.94 (brs, 1H), 5.64-5.69 (m, 1H), 7.34 (d, J=8.8 Hz,1H), 7.35-7.45 (m, 5H), 7.77 (dd, J1=8.8 Hz, J2=1.0 Hz, 1H), 8.38-8.42(m, 1H)

Example 30 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(pyrazol-3-yl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 30)

Hydrazine monohydrate (0.40 ml, 8.3 mmol) was added to a solution of 450mg (0.85 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(3-dimethylaminoacryloyl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 29) in 4 ml of tetrahydrofuran in an argon stream and themixture was stirred at 70° C. for 1 hour.

After the reaction was finished, water was added to the reactionsolution and the mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and concentrated in vacuo. Theresulting residue was subjected to a silica gel column chromatography(eluting solvent: n-hexane:ethyl acetate=1:1 to 1:2 (v/v)) and thefraction containing the aimed substance was concentrated in vacuo togive 430 mg of the title compound as yellow powder (yield:quantitative).

Melting point: 99 to 105° C. Rf value: 0.55 (ethyl acetate) Massspectrum (CI, m/z): 502 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.37(brs, 9H), 1.60-1.85 (m, 9H), 1.99-2.15 (m, 1H), 2.21-2.32 (m, 2H),3.73-3.82 (m, 1H), 4.09-4.17 (m, 1H), 4.93 (brs, 1H), 5.65-5.71 (m, 1H),6.07-6.12 (m, 1H), 7.20-7.38 (m, 5H), 7.46 (d, J=2.2 Hz, 1H), 7.75 (dd,J1=8.8 Hz, J2=1.0 Hz, 1H), 8.39-8.43 (m, 1H)

Example 31 Synthesis of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(isoxazol-5-yl)-1H-indazole(compound 31)

Hydroxylamine hydrochloride (150 mg, 2.2 mmol) and 150 mg (1.1 mmol) ofpotassium carbonate were added, in an argon stream, to a solution of 400mg (0.75 mmol) of5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(3-dimethylaminoacryloyl)-2-(tetrahydropyran-2-yl)-2H-indazole(compound 29) in 5 ml of ethanol and the mixture was heated to refluxfor 3 hours with stirring.

After the reaction was finished, the reaction solution was concentratedin vacuo, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue was subjected to a silicagel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1(v/v)) and the fraction containing the aimed substance was concentratedin vacuo to give 300 mg of the title compound as a pale yellow foamingsubstance (yield: 95%).

Rf value: 0.33 (n-hexane:ethyl acetate=1:1 (v/v)) Mass spectrum (CI,m/z): 419 (M⁺+1) ¹H-NMR spectrum (CDCl₃, δ ppm): 1.39 (brs, 9H), 1.68(s, 6H), 5.02 (brs, 1H), 5.48-5.60 (m, 1H), 7.21-7.28 (m, 2H), 7.40 (d,J=8.5 Hz, 1H), 7.41-7.48 (m, 2H), 7.55-7.62 (m, 1H), 8.09 (d, J=2.0 Hz,1H), 8.57 (s, 1H), 10.41 (brs, 1H)

Examples of Pharmaceutical Preparations

General examples of pharmaceutical preparations for the compounds of thepresent invention are as follows. 1) Tablets Formulation 1 (amounts in100 mg) Compound of the present invention 1 mg Lactose 66.4 mg Cornstarch 20 mg Carxboxymethyl cellulose calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg

The tablet having the above formulation is coated with 2 mg of a coatingagent (common coating agent such as hydroxypropyl methylcellulose,macrogol and silicone resin) to prepare an aimed coated tablet. Othertablets are also prepared in the same manner. Further, desired tabletsare able to be prepared when types and amounts of the compound of thepresent invention and of the additives are appropriately changed. 2)Capsules Formuation 2 (amounts in 150 mg) Compound of the presentinvention 5 mg Lactose 145 mg

Desired capsule preparations are able to be prepared when mixing ratioof the compound of the present invention to lactose are appropriatelychanged. 3) Eye drops Formuation 3 (amounts in 100 ml) Compound of thepresent invention 100 mg Sodium chloride 900 mg Polysorbate 80 200 mgSodium hydroxide q. s. Hydrochloric acid q. s. Sterilized purified waterq. s.

Desired eye drops are able to be prepared when types and amounts of thecompound and the additives are appropriately changed.

Pharmacological Tests

A. Test for Evaluation of Inhibiting Activity to Rho Kinase

In order to test the usefulness of the compounds of the presentinvention as a Rho kinase inhibitor, inhibiting activities of thecompounds of the present invention to Rho kinase were evaluated andinvestigated in accordance with the methods of Kaibuchi, et al.mentioned in J. Biol. Chem., 274, 32418, 1999 and also with the methodsmentioned in the instruction manual for use attached to commerciallyavailable activated ROCK II [Upstate Biotechnology, Catalog No. 14-338,(5 unite/50 μl)]. With regard to the test compounds, the compounds 5-1to 5-73 (except the compounds 5-2, 5-9, 5-18, 5-37 and 5-38) were used.

(Preparation of the Reagents)

1) Preparation of Buffer

A buffer was prepared so as to make tris(hydroxymethyl)aminomethane(Tris) (pH 7.5), 50 mM, ethyleneglycol bis(β-aminoethylether)-N,N,N′,N′-tetraacetic acid (EGTA), 2 mM,ethylenediaminetetraacetic acid (EDTA), 1 mM, magnesium chloride (MgCl₂)5 mM, β-glycerol phosphate, 5 mM, and dithiothreitol (DTT), 2 mM, bymixing them.

2) Preparation of 300 μM ATP [γ-³²P]ATP Solution

A mixed liquid of a 10 mM ATP solution with a commercially available[γ-³²P]ATP solution [NEN, Code No. NEG-002A] was diluted with the bufferto prepare a 300 μM ATP [γ-³²P]ATP solution.

3) Preparation of an Activated ROCK II Solution.

A commercially available activated ROCK II [Upstate Biotechnology,Catalog No. 14-338, (5 Units/50 μl)] was diluted to a concentration of1/100 with the buffer to prepare an activated ROCK II solution.

4) Preparation of a 1 mM Substrate Solution

A S6 Kinase Substrate Peptide [Upstate Biotechnology, Catalog No.12-124,] (2 mg) was dissolved in distilled water to prepare a 1 mMsubstrate solution.

5) Preparation of a Test Compound Solution

A test compound was dissolved in 10% aqueous dimethyl sulfoxidesolution.

(Method for Evaluation)

1) The test compound solution is placed in a microtube.

2) The 300 μM ATP [γ-³²P]ATP solution is added to the microtube followedby cooling to 4° C.

3) After that, a permanently activated ROCK II solution, 1 mM substratesolution and buffer are added to each microtube in that order, and thewhole is mixed and cooled again at 4° C.

4) The microtube is placed in an incubator (30° C.) and the mixture issubjected to reaction for 15 minutes.

5) After cooling to 4° C., a 250 mM phosphoric acid solution (5 μl) isadded to each microtube to stop the reaction.

6) The reaction solution (30 μl) is taken out from each microtube andspotted on a filter paper (Whatman P81) so that the reaction product(phosphorylated substrate) is adsorbed to the filter paper.

7) The filter paper is transferred to a beaker in which a 75 mMphosphoric acid solution is placed and shaken for 5 minutes so thatunreacted [γ-³²P]ATP is washed out. The washing operation as such iscarried out four times.

8) After that, the filter paper is dipped in ethanol to dehydrate andenergy amount (radioactivity) of the reaction product adsorbed to thefilter paper is measured with a liquid scintillation counter.

(Calculation of IC₅₀)

The IC₅₀ value was calculated by an XL-fit (IDBS).

(Calculation of Ki Value)

The Ki value is calculated by the following formula. S is an ATPconcentration contained in the reaction solution while Km is aMichaelis-Menten constant.Ki=IC ₅₀/(1+S/Km)

(Results and Considerations)

Result when the compounds 5-1 to 5-73 (except the compounds 5-2, 5-9,5-18, 5-37 and 5-38) were used as test compounds is shown in Table 1.TABLE 1 Test Compounds Ki Value (nM) Compound 5-1 19 Compound 5-3 20Compound 5-4 28 Compound 5-5 44 Compound 5-6 260 Compound 5-7 15Compound 5-8 97 Compound 5-10 134 Compound 5-11 144 Compound 5-12 7.5Compound 5-13 103 Compound 5-14 142 Compound 5-15 56 Compound 5-16 16Compound 5-17 199 Compound 5-19 55 Compound 5-20 61 Compound 5-21 26Compound 5-22 38 Compound 5-23 29 Compound 5-24 14 Compound 5-25 23Compound 5-26 27 Compound 5-27 86 Compound 5-28 15 Compound 5-29 2.7Compound 5-30 17 Compound 5-31 614 Compound 5-32 47 Compound 5-33 234Compound 5-34 294 Compound 5-35 139 Compound 5-36 35 Compound 5-39 12Compound 5-40 33 Compound 5-41 14 Compound 5-42 14 Compound 5-43 211Compound 5-44 13 Compound 5-45 27 Compound 5-46 27 Compound 5-47 45Compound 5-48 29 Compound 5-49 17 Compound 5-50 84 Compound 5-51 38Compound 5-52 14 Compound 5-53 3.6 Compound 5-54 31 Compound 5-55 13Compound 5-56 26 Compound 5-57 23 Compound 5-58 39 Compound 5-59 6.9Compound 5-60 35 Compound 5-61 45 Compound 5-62 126 Compound 5-63 241Compound 5-64 4.4 Compound 5-65 56 Compound 5-66 2.6 Compound 5-67 11Compound 5-68 6.4 Compound 5-69 55 Compound 5-70 28 Compound 5-71 34Compound 5-72 13 Compound 5-73 146

As is apparent from Table 1, all of the compounds of the presentinvention exhibited an excellent Rho kinase inhibiting action. From theabove-mentioned results, it was found that the compound of the presentinvention is very useful as a therapeutic agent for diseases in whichRho kinase is involved.

B. Test for Measuring the Intraocular Pressure-reducing Action

In order to check the usefulness of the compounds of the presentinvention as therapeutic agents for glaucoma, their intraocularpressure-reducing action when the compounds of the present inventionwere topically administered to cynomolgus monkeys (Macaca fascicularis)(sex: male; one group comprising 2 to 6 monkeys) was evaluated. Withregard to the test compounds, there were used the compound 5-3(hereinafter, referred to as a test compound 1), the compound 5-4(hereinafter, referred to as a test compound 2), the compound 5-42(hereinafter, referred to as a test compound 3) and the compound 5-44(hereinafter, referred to as a test compound 4).

(Preparation of a Test Compound Solution)

The test compounds 1, 2, 3 and 4 were dissolved in a 2.6% glycerolsolution, respectively, and sodium hydroxide was added thereto to adjustthe pH (pH 3.5 to 7.0) to prepare a test compound solution of a 1%concentration of the test compound 1, 2), a 0.3% concentration (of thetest compound 3) and a 0.1% concentration (of the test compound 4).

(Test Methods for Ocular Hypotension)

1) One drop of a 0.4% eyedrop of oxybuprocaine hydrochloride wasinstilled into each of both eyes of a cynomolgus monkey (Macacafascicularis) to induce local anesthesia.

2) Intraocular pressure was measured immediately before administrationof a test compound solution and defined as the initial intraocularpressure.

3) A test compound solution was instilled into one of the eyes of theexperimental animal (while another eye was not treated).

4) After 2, 4 and 6 hours after instillation of the test compoundsolution, one drop of a 0.4% eyedrop of oxybuprocaine hydrochloride wasinstilled into each of both eyes to induce local anesthesia and thenintraocular pressure was measured. The measuring intraocular pressurefor each time was carried out three times and a mean value thereof wascalculated.

As a control, only a vehicle (2.6% glycerol solution) instead of a testcompound solution was topically administered and the same test procedureas in the methods of the above 1) to 4) was conducted.

(Results and Considerations)

FIGS. 1, 2, 3 and 4 show the results when the test compounds 1, 2, 3 and4 were used, respectively. In Figs., the change in intraocular pressureshows the change from the initial intraocular pressure.

As apparent from FIGS. 1, 2, 3 and 4, all of the compounds of thepresent invention exhibited an excellent ocular hypotensive action. Fromthe above-mentioned results, it was found that the compound of thepresent invention is particularly useful as a therapeutic agent forglaucoma.

INDUSTRIAL APPLICABILITY

The present invention is to provide a novel indazole derivative or asalt thereof exhibiting a Rho kinase inhibiting action and being usefulas a therapeutic agent for diseases in which Rho kinase is involved suchas ocular diseases including glaucoma.

1. A compound represented by the following formula [I] or a saltthereof.

In the formula, a ring X is a benzene ring or a pyridine ring; R¹ and R²are, the same or different, hydrogen atom or a substituted orunsubstituted alkyl group; R¹ and R² can be bonded to form a substitutedor unsubstituted cycloalkane ring; R³ and R⁴ are, the same or different,one or more group(s) selected from the group consisting of halogen atom,hydrogen atom, hydroxyl group, a substituted or unsubstituted alkoxygroup, a substituted or unsubstituted alkenyloxy group, a substituted orunsubstituted alkynyloxy group, a substituted or unsubstitutedcycloalkyloxy group, a substituted or unsubstituted cycloalkenyloxygroup, a substituted or unsubstituted aryloxy group, a substituted orunsubstituted alkyl group, a substituted or unsubstituted alkenyl group,a substituted or unsubstituted alkynyl group, a substituted orunsubstituted cycloalkyl group, a substituted or unsubstitutedcycloalkenyl group, a substituted or unsubstituted aryl group, carboxylgroup or an ester or an amide thereof, hydrocarbonyl group, asubstituted or unsubstituted alkylcarbonyl group, a substituted orunsubstituted arylcarbonyl group, amino group, a substituted orunsubstituted alkylamino group, a substituted or unsubstituted arylaminogroup, mercapto group, a substituted or unsubstituted alkylthio group, asubstituted or unsubstituted arylthio group, sulfinic acid group or anester or an amide thereof, hydrosulfinyl group, a substituted orunsubstituted alkylsulfinyl group, a substituted or unsubstitutedarylsulfinyl group, sulfonic acid group or an ester or an amide thereof,hydrosulfonyl group, a substituted or unsubstituted alkylsulfonyl group,a substituted or unsubstituted arylsulfonyl group, nitro group, cyanogroup and a substituted or unsubstituted monocyclic heterocylic group;R⁵ is one or more group(s) selected from the group consisting of halogenatom, hydrogen atom, hydroxyl group, a substituted or unsubstitutedalkoxy group, a substituted or unsubstituted aryloxy group, asubstituted or unsubstituted alkyl group and a substituted orunsubstituted aryl group.
 2. The compound according to claim 1, whereinthe substituted alkoxy group, the substituted alkyl group, thesubstituted alkenyl group or the substituted aryl group is an alkoxygroup, an alkyl group, an alkenyl group or an aryl group substitutedwith one or more group(s) selected from the group consisting of halogenatom, hydroxyl group, an unsubstituted alkoxy group, an unsubstitutedaryl group, hydroxyimino group and an unsubstituted alkoxyimino group,or a salt thereof.
 3. The compound according to claim 1 or 2, wherein,in the formula [I], the ring X is benzene ring or pyridine ring; R¹ andR² are hydrogen atom or alkyl group; R¹ and R² are bonded to form anunsubstituted cycloalkane ring; R³ is hydrogen atom, a substituted alkylgroup, an unsubstituted alkenyl group, carboxyl group or an ester or anamide thereof, amino group or cyano group; R⁴ is hydrogen atom, hydroxylgroup, a substituted or unsubstituted alkoxy group, an unsubstitutedalkenyloxy group, an unsubstituted cycloalkyloxy group, a substituted orunsubstituted alkyl group, an unsubstituted alkenyl group, anunsubstituted cycloalkyl group, amino group, an unsubstituted alkylaminogroup, nitro group, cyano group or a monocyclic heterocycle group; andR⁵ is halogen atom or hydrogen atom ,or a salt thereof.
 4. The compoundaccording to claim 3, wherein the substituted alkoxy group is an alkoxygroup substituted with halogen atom and the substituted alkyl group isan alkyl group substituted with one or more group(s) selected from thegroup consisting of hydroxyl group and hydroxyimino group, or a saltthereof.
 5. The compound according to any of claims 1 to 4, wherein, inthe formula [I], the ring X is benzene ring or pyridine ring; R¹ and R²are hydrogen atom, methyl group or ethyl group; R¹ and R² can be bondedto form a cyclopentane ring; R³ is hydrogen atom, hydroxymethyl group,hydroxyiminomethyl group, 1-methylvinyl group, carboxyl group,methoxycarbonyl group, aminocarbonyl group, amino group or cyano group;R⁴ is hydrogen atom, hydroxyl group, methoxy group, ethoxy group,n-propyloxy group, n-butyloxy group, isopropyloxy group, difluoromethoxygroup, 2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, allyloxygroup, cyclopropyloxy group, cyclopropylmethyloxy group, ethyl group,vinyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethylgroup, cyclopropyl group, amino group, methylamino group, dimethylaminogroup, diethylamino group, nitro group, cyano group, pyrrolidine ring,pyrrole ring, pyrazole ring, oxazole ring, isoxazole ring, piperidinering, pyridine ring or morpholine ring; and R⁵ is chlorine atom orhydrogen atom or a salt thereof.
 6. The compound according to any ofclaims 1 to 5, wherein the ring X is substituted at 5-position of theindazole ring in the formula [I] or a salt thereof.
 7. A compoundselected from the group consisting of the following or a salt thereof.5-[4-(1-Amino-1-methylethyl)phenyl]-1H-indazole1-Acetyl-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-nitro-1H-indazole4-Amino-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-benzylamino-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-methylamino-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-3-methoxycarbonyl-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-3-carboxy-1H-indazole3-Aminocarbonyl-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole3-Amino-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-3-hydroxyiminomethyl-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-3-cyano-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-3-hydroxymethyl-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-3-(1-methylvinyl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-dimethylamino-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-nitro-1H-indazole4-(N-Acetylamino)-5-[4-(1-amino-1-methylethyl)-phenyl]-1H-indazole5-[4-(Aminomethyl)phenyl]-4-nitro-1H-indazole4-Amino-5-[4-(aminomethyl)phenyl]-1H-indazole4-Amino-5-[4-(1-aminocyclopentyl)phenyl]-1H-indazole4-Amino-5-[4-(1-amino-1-ethylpropyl)phenyl]-1H-indazole5-[4-(Aminomethyl)phenyl]-4-dimethylamino-1H-indazole5-[4-(1-Aminocyclopentyl)phenyl]-4-dimethylamino-1H-indazole5-[4-(1-Amino-1-ethylpropyl)phenyl]-4-dimethyl-amino-1H-indazole5-[4-(1-Aminoethyl)phenyl]-4-dimethylamino-1H-indazole5-[5-(1-Amino-1-methylethyl)-3-chloropyridin-2-yl]-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-ethyl-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-cyclopropyl-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-vinyl-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-diethylamino-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(2-hydroxyethyl)-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-(2-hydroxyethyl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(1-hydroxyethyl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-hydroxymethyl-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-cyano-1H-indazole6-[4-(1-Amino-1-methylethyl)phenyl]-1H-indazole1-Acetyl-6-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrrol-1-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-isopropoxy-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(piperidin-1-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrrolidin-1-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(morpholin-4-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-methoxy-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-methoxy-1H-indazole5-[5-(1-Aminocyclopentyl)pyridin-2-yl]-4-methoxy-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-ethoxy-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-hydroxy-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-ethoxy-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-isopropoxy-1H-indazole5-[5-(1-Amino-1-ethylpropyl)pyridin-2-yl]-4-methoxy-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-n-propoxy-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-difluoromethoxy-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(2,2,2-trifluoroethoxy)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-n-butoxy-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(2-fluoroethoxy)-1H-indazole4-Allyloxy-5-[4-(1-amino-1-methylethyl)phenyl]-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-n-propoxy-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-difluoromethoxy-1H-indazole5-[5-(1-Amino-1-ethylpropyl)pyridin-2-yl]-4-ethoxy-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyridin-4-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyridin-3-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyridin-2-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrazol-4-yl)-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-(pyrazol-4-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(oxazol-5-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(pyrazol-3-yl)-1H-indazole5-[4-(1-Amino-1-methylethyl)phenyl]-4-(isoxazol-5-yl)-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-hydroxyl-1H-indazole5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-cyclopropyloxy-1H-indazole5-[5-(1-Amino-1-ethylpropyl)pyridin-2-yl]-4-cyclopropyloxy-1H-indazole5-[4-(1-Amino-1-ethylpropyl)phenyl]-4-difluoromethoxy-1H-indazole and5-[5-(1-Amino-1-methylethyl)pyridin-2-yl]-4-cyclopropylmethyloxy-1H-indazole.8. A pharmaceutical composition comprising the compound according to anyof claims 1 to 7 or a salt thereof.
 9. A Rho kinase inhibitor comprisingthe compound according to any of claims 1 to 7 or a salt thereof as anactive ingredient.
 10. A therapeutic agent for glaucoma comprising thecompound according to any of claims 1 to 7 or a salt thereof as anactive ingredient.